Is OTX2 p.Ser153= (c.459C>T) pathogenic?

OTX2 p.Ser153= (c.459C>T) is classified Benign/Likely benign in OTX2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-15). Low-frequency (popmax 3.13%, afr); Associated with pituitary hormone deficiency, combined, 6.

What condition is associated with OTX2 p.Ser153= (c.459C>T)?

OTX2 p.Ser153= (c.459C>T) is associated with pituitary hormone deficiency, combined, 6, syndromic microphthalmia type 5 (ClinVar).

How common is OTX2 p.Ser153= (c.459C>T) in the general population?

OTX2 p.Ser153= (c.459C>T) is low-frequency (popmax 3.13%, afr) (gnomAD).

OTX2 p.Ser153=

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.459C>T · rs34537598 · VCV313417

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.13%, afr)

Conditions

pituitary hormone deficiency, combined, 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 1.7, phastCons 1
Overall
CADD	11.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.13% African / African-American · 2,348/75,016 alleles

Filtering AF 3.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.98%

Overall 0.165% 2,659/1,614,094 alleles · low-frequency exomes 1,316/1,461,814 · genomes 1,343/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.13%	32
Middle Eastern	0.264%	379
Remaining individualsnot grpmax-eligible	0.222%	450
Admixed American	0.185%	541
South Asian	0.00878%	11,386
European (non-Finnish)	0.00314%	31,891

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.Ser153=
Coding: c.459C>T
MANE Select: NM_021728
dbSNP: rs34537598
Type: single nucleotide variant
Location: chr14:56802170 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99

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.Ser153Arg Uncertain significance ★ ⚠ same residue
OTX2 p.Ser153Asn Uncertain significance ★ ⚠ same residue
OTX2 p.Glu87Lys Pathogenic/Likely pathogenic ★★ same condition
OTX2 p.Tyr197Ter Pathogenic/Likely pathogenic ★★ same condition
OTX2 p.Arg127Leu Uncertain significance ★★ 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-ser153 (accessed [today's date]).

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