Is OPLAH p.Pro657Ser (c.1969C>T) pathogenic?

OPLAH p.Pro657Ser (c.1969C>T) is classified Uncertain significance in OPLAH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-19). AlphaMissense: likely benign (0.1773); Very rare (popmax 0.00169%, amr).

How common is OPLAH p.Pro657Ser (c.1969C>T) in the general population?

OPLAH p.Pro657Ser (c.1969C>T) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about OPLAH p.Pro657Ser (c.1969C>T)?

AlphaMissense predicts likely benign (score 0.1773) — an in-silico prediction, not a clinical call.

OPLAH p.Pro657Ser

c.1969C>T · rs1304541939 · VCV2272429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1773	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -11.90	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,706 bp · p 0.038 · regional, not allelic
Overall
CADD	24.1	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 0.00169% Admixed American · 1/59,168 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000436% 7/1,606,062 alleles · very rare exomes 6/1,453,858 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,168
European (non-Finnish)	0.00051%	196,158

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: OPLAH
Protein: p.Pro657Ser
Coding: c.1969C>T
MANE Select: NM_017570
dbSNP: rs1304541939
Type: single nucleotide variant
Location: chr8:144056399 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.08

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

Similar variants

OPLAH p.Pro657= Conflicting classifications of pathogenicity ★ same residue
OPLAH p.Pro657Ala Uncertain significance ★ ⚠ same residue
OPLAH c.587+1G>A Pathogenic/Likely pathogenic ★★ same type
OPLAH p.Gln1006Ter Pathogenic/Likely pathogenic ★★ same type
OPLAH p.Tyr248Ter Likely pathogenic ★★ same type
OPLAH p.Ala1093Val Uncertain significance ★★ ⚠ same type
OPLAH p.Ala344Thr Uncertain significance ★★ ⚠ same type
OPLAH p.Ala422Val Uncertain significance ★★ ⚠ 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/oplah-p-pro657ser (accessed [today's date]).

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