Is OPA1 p.Phe649Ser (c.1946T>C) pathogenic?

OPA1 p.Phe649Ser (c.1946T>C) is classified Uncertain significance in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2015-09-01). AlphaMissense: likely pathogenic (0.9902); No allele count reported in gnomAD v4.1 (AN 1,601,544).

How common is OPA1 p.Phe649Ser (c.1946T>C) in the general population?

OPA1 p.Phe649Ser (c.1946T>C) is no allele count reported in gnomAD v4.1 (AN 1,601,544) (gnomAD).

What do computational predictors say about OPA1 p.Phe649Ser (c.1946T>C)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

OPA1 p.Phe649Ser

c.1946T>C · rs886042514 · VCV282900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,601,544)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -13.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F594S vs ClinVar F649S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,601,544). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: OPA1
Protein: p.Phe649Ser
Coding: c.1946T>C
MANE Select: NM_130837
dbSNP: rs886042514
Type: single nucleotide variant
Location: chr3:193648805 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 594 UniProt numbering: the 'stalk region' region

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

Similar variants

OPA1 p.Phe649fs Pathogenic ★ same residue
OPA1 c.1035+1G>A Pathogenic ★★ same type
OPA1 c.1035+5G>A Pathogenic/Likely pathogenic ★★ same type
OPA1 c.1149+1G>A Pathogenic ★★ same type
OPA1 c.1149+1G>T Likely pathogenic ★★ same type
OPA1 c.1150-2A>G Pathogenic ★★ same type
OPA1 c.1230+1G>A Pathogenic ★★ same type
OPA1 c.1230+5G>A Pathogenic/Likely pathogenic ★★ same type

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-phe649ser (accessed [today's date]).

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