MYOC p.Pro481Ser
c.1441C>T · rs763068244 · VCV1686786
ClinGen expert panel — Glaucoma VCEP
Uncertain Significance for open-angle glaucoma. Applied ACMG criteria (verbatim):
PM2_Supporting PP3
Curation rationale (ClinGen, verbatim)
The c.1441C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Serine at amino acid 481 (p.Pro481Ser). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00008911 (4 alleles out of 44,888), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.684, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. The Pro481Ser protein was assessed in an assay (PMID: 35196929), however, the results for this protein were inconsistent and not included as evidence. Only 1 proband with primary open angle glaucoma had been reported (PMID: 15534471), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3412 | ambiguous |
|---|---|---|
| REVEL | 0.684 | pathogenic-leaning |
| SaProt | LLR -7.04 | tolerated |
| ⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | phastCons 1 |
| Regional constraint | o/e 0.92 | unconstrained · MANE · 17 kb · p 0.038 · regional, not allelic |
| Overall | ||
| CADD | 26.8 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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
- MYOC
- Protein
- p.Pro481Ser
- Coding
- c.1441C>T
- MANE Select
- NM_000261
- dbSNP
- rs763068244
- Type
- single nucleotide variant
- Location
- chr1:171635999 (GRCh38)
- Gene constraint
- LOEUF 1.343 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.40 · 24 PDB
- Residue 481
- a UniProt-annotated variant site (in glc1a); a UniProt-annotated variant site (in glc1a; uncertain significance); a turn; the olfactomedin-like domain
Similar variants
- MYOC p.Pro481Leu Likely pathogenic ★★★ ⚠ same residue
- MYOC p.Pro481Arg Uncertain significance ★★★ ⚠ same residue
- MYOC p.Pro481Thr Uncertain significance ★★★ ⚠ same residue
- MYOC p.Ala363Thr Likely pathogenic ★★★ same condition
- MYOC p.Arg272Gly Likely pathogenic ★★★ same condition
- MYOC p.Asn450Tyr Likely pathogenic ★★★ same condition
- MYOC p.Asn480Lys Pathogenic ★★★ same condition
- MYOC p.Asp380Ala 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/myoc-p-pro481ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown