Is CARD6 p.Val239Ala (c.716T>C) pathogenic?

CARD6 p.Val239Ala (c.716T>C) is classified Uncertain significance in CARD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0371%, nfe).

How common is CARD6 p.Val239Ala (c.716T>C) in the general population?

CARD6 p.Val239Ala (c.716T>C) is ultra-rare (popmax 0.0371%, nfe) (gnomAD).

What do computational predictors say about CARD6 p.Val239Ala (c.716T>C)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

CARD6 p.Val239Ala

c.716T>C · rs61757655 · VCV3137341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0371%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -5.84	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 -0.89	GERP -3.7
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.91 · regional, not allelic
Overall
CADD	0.323	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 0.0371% European (non-Finnish) · 437/1,179,284 alleles

Filtering AF 0.0342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.0296% 477/1,611,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0371%	2,699
Admixed American	0.0355%	2,818
Remaining individualsnot grpmax-eligible	0.0289%	3,465
African / African-American	0.00134%	74,620

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: CARD6
Protein: p.Val239Ala
Coding: c.716T>C
MANE Select: NM_032587
dbSNP: rs61757655
Type: single nucleotide variant
Location: chr5:40843584 (GRCh38)
Gene constraint: LOEUF 1.487 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.25
Residue 239: the 'disordered' region

Full CARD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARD6 p.Val239Ile Likely benign ★ same residue
CARD6 p.Arg93Lys Benign ★★ same type
CARD6 p.Cys185Tyr Benign ★★ same type
CARD6 p.Gly264Glu Benign ★★ same type
CARD6 p.Ile194Val Benign ★★ same type
CARD6 p.Ala1022Asp Uncertain significance ★ ⚠ same type
CARD6 p.Ala110Thr Conflicting classifications of pathogenicity ★ ⚠ same type
CARD6 p.Ala159Thr 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/card6-p-val239ala (accessed [today's date]).

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