Is CARD10 p.Val75Ile (c.223G>A) pathogenic?

CARD10 p.Val75Ile (c.223G>A) is classified Uncertain significance in CARD10 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1169); Very rare (popmax 8.71e-05%, nfe).

How common is CARD10 p.Val75Ile (c.223G>A) in the general population?

CARD10 p.Val75Ile (c.223G>A) is very rare (popmax 8.71e-05%, nfe) (gnomAD).

What do computational predictors say about CARD10 p.Val75Ile (c.223G>A)?

AlphaMissense predicts likely benign (score 0.1169) — an in-silico prediction, not a clinical call.

CARD10 p.Val75Ile

c.223G>A · VCV4648254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.71e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1169	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.85	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 1	GERP -1.6, phastCons 0.9
Regional constraint	o/e 0.63	unconstrained · MANE · 2,983 bp · p 6e-08 · regional, not allelic
Overall
CADD	20.6	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 8.71e-05% European (non-Finnish) · 1/1,148,082 alleles

Overall 7.18e-05% 1/1,391,870 alleles · very 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: CARD10
Protein: p.Val75Ile
Coding: c.223G>A
MANE Select: NM_014550
Type: single nucleotide variant
Location: chr22:37518978 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.22
Residue 75: the card domain

Full CARD10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARD10 p.Thr436Met Uncertain significance ★★ ⚠ same type
CARD10 p.Ala382Thr Benign ★★ same type
CARD10 p.Glu327= Likely benign ★★ same type
CARD10 p.Ile940= Benign/Likely benign ★★ same type
CARD10 p.Lys514Arg Benign ★★ same type
CARD10 p.Thr383= Benign ★★ same type
CARD10 p.Arg420Cys Likely pathogenic ★ ⚠ same type
CARD10 c.2864+2T>G 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/card10-p-val75ile (accessed [today's date]).

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