Is CD58 p.Val63Ala (c.188T>C) pathogenic?

CD58 p.Val63Ala (c.188T>C) is classified Uncertain significance in CD58 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: ambiguous (0.445); Ultra-rare (popmax 0.0111%, eas).

How common is CD58 p.Val63Ala (c.188T>C) in the general population?

CD58 p.Val63Ala (c.188T>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CD58 p.Val63Ala (c.188T>C)?

AlphaMissense predicts ambiguous (score 0.445) — an in-silico prediction, not a clinical call.

CD58 p.Val63Ala

c.188T>C · VCV3998291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.445 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.445	ambiguous
REVEL	0.077	moderately benign-leaning
SaProt	LLR -9.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.28, phastCons 0.04
Regional constraint	o/e 0.89	unconstrained · MANE · 56 kb · p 0.052 · regional, not allelic
Overall
CADD	17.43	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 0.0111% East Asian · 5/44,860 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000342% 5/1,461,794 alleles · ultra-rare

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: CD58
Protein: p.Val63Ala
Coding: c.188T>C
MANE Select: NM_001779
Type: single nucleotide variant
Location: chr1:116544487 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI 0.35 (gnomAD)
Structure: AlphaFold pLDDT 83.54 · 3 PDB
Residue 63: a β-strand; the ig-like domain

Full CD58 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD58 p.Ala224Ser Uncertain significance ★ ⚠ same type
CD58 p.Ala7Glu Uncertain significance ★ ⚠ same type
CD58 p.Arg168Pro Uncertain significance ★ ⚠ same type
CD58 p.Arg246Gly Uncertain significance ★ ⚠ same type
CD58 p.Asn135Thr Uncertain significance ★ ⚠ same type
CD58 p.Asn179Asp Uncertain significance ★ ⚠ same type
CD58 p.Asn48Asp Uncertain significance ★ ⚠ same type
CD58 p.Cys229Tyr 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/cd58-p-val63ala (accessed [today's date]).

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