Is CCR5 p.Val25Glu (c.74T>A) pathogenic?

CCR5 p.Val25Glu (c.74T>A) is classified Uncertain significance in CCR5 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-26). AlphaMissense: ambiguous (0.3994); Ultra-rare (popmax 0.0822%, mid).

How common is CCR5 p.Val25Glu (c.74T>A) in the general population?

CCR5 p.Val25Glu (c.74T>A) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about CCR5 p.Val25Glu (c.74T>A)?

AlphaMissense predicts ambiguous (score 0.3994) — an in-silico prediction, not a clinical call.

CCR5 p.Val25Glu

c.74T>A · rs751650495 · VCV2636002

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3994	ambiguous
REVEL	0.21	benign-leaning
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,055 bp · p 0.04 · regional, not allelic
Overall
CADD	18.72	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 0.0822% Middle Eastern · 5/6,080 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00471% 76/1,613,632 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,216
African / African-American	0.0294%	3,406
Remaining individualsnot grpmax-eligible	0.0208%	4,806
Admixed American	0.00834%	11,996
South Asian	0.0033%	30,342
European (non-Finnish)	0.00237%	42,134

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: CCR5
Protein: p.Val25Glu
Coding: c.74T>A
MANE Select: NM_001394783
dbSNP: rs751650495
Type: single nucleotide variant
Location: chr3:46372976 (GRCh38)
Gene constraint: LOEUF 1.592 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 85.41 · 26 PDB
Residue 25: a disulfide bond; an α-helix

Full CCR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCR5 p.Ser63Cys Uncertain significance ★★ ⚠ same type
CCR5 p.Ala298Asp Uncertain significance ★ ⚠ same type
CCR5 p.Ala91Val Uncertain significance ★ ⚠ same type
CCR5 p.Ala92Thr Uncertain significance ★ ⚠ same type
CCR5 p.Arg168Gly Uncertain significance ★ ⚠ same type
CCR5 p.Arg274Lys Uncertain significance ★ ⚠ same type
CCR5 p.Arg31His Uncertain significance ★ ⚠ same type
CCR5 p.Arg341Gln 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/ccr5-p-val25glu (accessed [today's date]).

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