Is REV1 p.Arg752His (c.2255G>A) pathogenic?

REV1 p.Arg752His (c.2255G>A) is classified Uncertain significance in REV1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely benign (0.2075); Very rare (popmax 0.00267%, afr).

How common is REV1 p.Arg752His (c.2255G>A) in the general population?

REV1 p.Arg752His (c.2255G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about REV1 p.Arg752His (c.2255G>A)?

AlphaMissense predicts likely benign (score 0.2075) — an in-silico prediction, not a clinical call.

REV1 p.Arg752His

c.2255G>A · rs1322536048 · VCV3153211

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2075	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 24 kb · p 5.1e-07 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,774 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000868% 14/1,612,612 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,387
East Asian	0.00223%	44,844
Admixed American	0.00168%	59,696
European (non-Finnish)	0.000848%	117,963

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.Arg752His
Coding: c.2255G>A
MANE Select: NM_016316
dbSNP: rs1322536048
Type: single nucleotide variant
Location: chr2:99410785 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.20 · 17 PDB
Residue 752: a β-strand

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-arg752his (accessed [today's date]).

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