Is OTX2 p.Arg127Pro (c.380G>C) pathogenic?

OTX2 p.Arg127Pro (c.380G>C) is classified Conflicting classifications of pathogenicity in OTX2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-11-17). AlphaMissense: likely benign (0.3301); Very rare (popmax 0.00667%, amr); Associated with pituitary hormone deficiency, combined, 6.

What condition is associated with OTX2 p.Arg127Pro (c.380G>C)?

OTX2 p.Arg127Pro (c.380G>C) is associated with pituitary hormone deficiency, combined, 6, syndromic microphthalmia type 5 (ClinVar).

How common is OTX2 p.Arg127Pro (c.380G>C) in the general population?

OTX2 p.Arg127Pro (c.380G>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about OTX2 p.Arg127Pro (c.380G>C)?

AlphaMissense predicts likely benign (score 0.3301) — an in-silico prediction, not a clinical call.

OTX2 p.Arg127Pro

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.380G>C · rs199799627 · VCV313419

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3301 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pituitary hormone deficiency, combined, 6

Computational evidence

Protein change
AlphaMissense	0.3301	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -3.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 557 bp · p 0.76 · regional, not allelic
Overall
CADD	22.1	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 R119P vs ClinVar R127P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,998 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000682% 11/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
European (non-Finnish)	0.000593%	168,577

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.Arg127Pro
Coding: c.380G>C
MANE Select: NM_021728
dbSNP: rs199799627
Type: single nucleotide variant
Location: chr14:56802249 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 127: 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

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

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

Similar variants

OTX2 p.Arg127Leu Uncertain significance ★★ same residue
OTX2 p.Arg127Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
OTX2 p.Arg127Trp Uncertain significance ★ ⚠ same residue
OTX2 p.Glu87Lys Pathogenic/Likely pathogenic ★★ same condition
OTX2 p.Tyr197Ter Pathogenic/Likely pathogenic ★★ same condition
OTX2 p.Arg48Trp Uncertain significance ★★ ⚠ same condition
OTX2 p.His238Leu Uncertain significance ★★ ⚠ same condition
OTX2 c.97+12C>T Benign/Likely benign ★★ 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-arg127pro (accessed [today's date]).

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