Is REV1 p.Ser658Pro (c.1972T>C) pathogenic?

REV1 p.Ser658Pro (c.1972T>C) is classified Uncertain significance in REV1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: ambiguous (0.5375); Ultra-rare (popmax 0.0141%, nfe).

How common is REV1 p.Ser658Pro (c.1972T>C) in the general population?

REV1 p.Ser658Pro (c.1972T>C) is ultra-rare (popmax 0.0141%, nfe) (gnomAD).

What do computational predictors say about REV1 p.Ser658Pro (c.1972T>C)?

AlphaMissense predicts ambiguous (score 0.5375) — an in-silico prediction, not a clinical call.

REV1 p.Ser658Pro

c.1972T>C · rs765459821 · VCV2356100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5375	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -9.85	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP -0.69, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 24 kb · p 5.1e-07 · regional, not allelic
Overall
CADD	22.0	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 0.0141% European (non-Finnish) · 166/1,179,364 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0117% 188/1,613,364 alleles · ultra-rare exomes 171/1,461,132 · genomes 17/152,232 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0141%	7,105
Admixed American	0.0117%	8,573
Remaining individualsnot grpmax-eligible	0.008%	12,493
South Asian	0.00769%	13,011
African / African-American	0.00267%	37,471
Finnishnot grpmax-eligible	0.00156%	64,032

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: REV1
Protein: p.Ser658Pro
Coding: c.1972T>C
MANE Select: NM_016316
dbSNP: rs765459821
Type: single nucleotide variant
Location: chr2:99412931 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.20 · 17 PDB
Residue 658: an α-helix

Full REV1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

REV1 p.Leu1131His Benign ★★ same type
REV1 p.Ala335Thr Uncertain significance ★ ⚠ same type
REV1 p.Ala494Val Uncertain significance ★ ⚠ same type
REV1 p.Ala581Gly Uncertain significance ★ ⚠ same type
REV1 p.Ala789Thr Uncertain significance ★ ⚠ same type
REV1 p.Ala907Asp Uncertain significance ★ ⚠ same type
REV1 p.Arg219Ser Uncertain significance ★ ⚠ same type
REV1 p.Arg290Gln 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/rev1-p-ser658pro (accessed [today's date]).

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