Is OTX2 p.Pro142Arg (c.425C>G) pathogenic?

OTX2 p.Pro142Arg (c.425C>G) is classified Conflicting classifications of pathogenicity in OTX2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.3087); Ultra-rare (popmax 0.0467%, amr); Associated with pituitary hormone deficiency, combined, 6.

What condition is associated with OTX2 p.Pro142Arg (c.425C>G)?

OTX2 p.Pro142Arg (c.425C>G) is associated with pituitary hormone deficiency, combined, 6, syndromic microphthalmia type 5, 46,XY partial gonadal dysgenesis (ClinVar).

How common is OTX2 p.Pro142Arg (c.425C>G) in the general population?

OTX2 p.Pro142Arg (c.425C>G) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

What do computational predictors say about OTX2 p.Pro142Arg (c.425C>G)?

AlphaMissense predicts likely benign (score 0.3087) — an in-silico prediction, not a clinical call.

OTX2 p.Pro142Arg

Q: How is Combined pituitary hormone deficiencies, genetic forms inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.425C>G · rs199761861 · VCV803030

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.3087 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pituitary hormone deficiency, combined, 6

Computational evidence

Protein change
AlphaMissense	0.3087	likely benign
REVEL	0.741	pathogenic-leaning
SaProt	LLR -9.65	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 557 bp · p 0.76 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P134R vs ClinVar P142R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% Admixed American · 28/60,012 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.0228% 368/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0467%	2,143
European (non-Finnish)	0.0271%	3,688
Remaining individualsnot grpmax-eligible	0.0192%	5,209
African / African-American	0.00667%	15,004
East Asian	0.00223%	44,880
South Asian	0.0022%	45,536

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: OTX2
Protein: p.Pro142Arg
Coding: c.425C>G
MANE Select: NM_021728
dbSNP: rs199761861
Type: single nucleotide variant
Location: chr14:56802204 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 134 UniProt numbering: a UniProt-annotated variant site (in mcops5); a UniProt-annotated variant site (in cphd6; uncertain significance; loss of transcriptional activity, when tested on bicoid binding sites; decreases transactivation mediated by the wild-type protein, when tested on bicoid binding sites; no effect on dna-binding); the 'disordered' region

Full OTX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pituitary hormone deficiency, combined, 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: syndromic microphthalmia type 5 46,XY partial gonadal dysgenesis inherited retinal dystrophy

For Combined pituitary hormone deficiencies, genetic forms (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

OTX2 p.Pro142Ala Uncertain significance ★★ ⚠ same residue
OTX2 p.Pro142= Likely benign ★★ same residue
OTX2 p.Pro142His Uncertain significance ★ ⚠ same residue
OTX2 p.Pro142Leu Uncertain significance ★ ⚠ same residue
OTX2 p.Pro142Ser Uncertain significance ★ ⚠ same residue
OTX2 p.Pro142Thr Uncertain significance ★ ⚠ same residue
OTX2 p.Glu87Lys Pathogenic/Likely pathogenic ★★ same condition
OTX2 p.Tyr197Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/otx2-p-pro142arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown