Is CARD6 p.Phe543Ser (c.1628T>C) pathogenic?

CARD6 p.Phe543Ser (c.1628T>C) is classified Uncertain significance in CARD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely pathogenic (0.7337); Very rare (popmax 0.00133%, afr).

How common is CARD6 p.Phe543Ser (c.1628T>C) in the general population?

CARD6 p.Phe543Ser (c.1628T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CARD6 p.Phe543Ser (c.1628T>C)?

AlphaMissense predicts likely pathogenic (score 0.7337) — an in-silico prediction, not a clinical call.

CARD6 p.Phe543Ser

c.1628T>C · VCV3484990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7337	likely pathogenic · top 4% in CARD6
REVEL	0.172	moderately benign-leaning
SaProt	LLR -13.60	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.91 · regional, not allelic
Overall
CADD	22.5	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 0.00133% African / African-American · 1/75,050 alleles

Overall 6.84e-05% 1/1,461,890 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: CARD6
Protein: p.Phe543Ser
Coding: c.1628T>C
MANE Select: NM_032587
Type: single nucleotide variant
Location: chr5:40852960 (GRCh38)
Gene constraint: LOEUF 1.487 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.25

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

Similar variants

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
CARD6 p.Ala340Thr 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-phe543ser (accessed [today's date]).

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