Is OPA1 p.Leu17Ser (c.50T>C) pathogenic?

OPA1 p.Leu17Ser (c.50T>C) is classified Uncertain significance in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1425); Very rare (popmax 0.00167%, amr).

How common is OPA1 p.Leu17Ser (c.50T>C) in the general population?

OPA1 p.Leu17Ser (c.50T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about OPA1 p.Leu17Ser (c.50T>C)?

AlphaMissense predicts likely benign (score 0.1425) — an in-silico prediction, not a clinical call.

OPA1 p.Leu17Ser

c.50T>C · VCV4774381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1425 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1425	likely benign
REVEL	0.651	pathogenic-leaning
SaProt	LLR -6.05	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Overall
CADD	24.2	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 0.00167% Admixed American · 1/60,028 alleles

Overall 0.000124% 2/1,613,598 alleles · very rare exomes 2/1,461,242 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
South Asian	0.0011%	91,078

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.Leu17Ser
Coding: c.50T>C
MANE Select: NM_130837
Type: single nucleotide variant
Location: chr3:193614740 (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

Similar variants

OPA1 p.Leu17Ile Uncertain significance ★★ ⚠ 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-leu17ser (accessed [today's date]).

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