Is OPA1 p.Pro157Ser (c.469C>T) pathogenic?

OPA1 p.Pro157Ser (c.469C>T) is classified Uncertain significance in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely benign (0.2433); Very rare (popmax 6.87e-05%); Associated with OPA1-related disorder.

What condition is associated with OPA1 p.Pro157Ser (c.469C>T)?

OPA1 p.Pro157Ser (c.469C>T) is associated with OPA1-related disorder (ClinVar).

How common is OPA1 p.Pro157Ser (c.469C>T) in the general population?

OPA1 p.Pro157Ser (c.469C>T) is very rare (popmax 6.87e-05%) (gnomAD).

What do computational predictors say about OPA1 p.Pro157Ser (c.469C>T)?

AlphaMissense predicts likely benign (score 0.2433) — an in-silico prediction, not a clinical call.

OPA1 p.Pro157Ser

c.469C>T · rs2474598574 · VCV2630267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.87e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

OPA1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2433	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -11.74	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.87e-05%

Overall 6.87e-05% 1/1,455,632 alleles · very rare

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: OPA1
Protein: p.Pro157Ser
Coding: c.469C>T
MANE Select: NM_130837
dbSNP: rs2474598574
Type: single nucleotide variant
Location: chr3:193617198 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB

Full OPA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

OPA1-related disorder

Similar variants

OPA1 c.1149+1G>A Pathogenic ★★ same condition
OPA1 c.1230+5G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1305+1G>T Pathogenic ★★ same condition
OPA1 c.1377+1G>A Pathogenic ★★ same condition
OPA1 c.2012+1G>T Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2178+1G>A Pathogenic ★★ same condition
OPA1 c.2661+1G>T Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2661+2T>C 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/opa1-p-pro157ser (accessed [today's date]).

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