Is CLEC6A p.Val192Phe (c.574G>T) pathogenic?

CLEC6A p.Val192Phe (c.574G>T) is classified Uncertain significance in CLEC6A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: ambiguous (0.3922); Ultra-rare (popmax 0.0117%, amr).

How common is CLEC6A p.Val192Phe (c.574G>T) in the general population?

CLEC6A p.Val192Phe (c.574G>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CLEC6A p.Val192Phe (c.574G>T)?

AlphaMissense predicts ambiguous (score 0.3922) — an in-silico prediction, not a clinical call.

CLEC6A p.Val192Phe

c.574G>T · VCV3267706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3922	ambiguous
REVEL	0.179	moderately benign-leaning
SaProt	LLR -8.43	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 3.9	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 21 kb · p 0.84 · regional, not allelic
Overall
CADD	22.4	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 0.0117% Admixed American · 7/59,788 alleles

Filtering AF 0.00545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000685% 10/1,459,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,541
Remaining individualsnot grpmax-eligible	0.0032%	31,211
European (non-Finnish)	8.49e-05%	1,178,456

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: CLEC6A
Protein: p.Val192Phe
Coding: c.574G>T
MANE Select: NM_001007033
Type: single nucleotide variant
Location: chr12:8477408 (GRCh38)
Gene constraint: LOEUF 1.267 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.21 · 2 PDB
Residue 192: a disulfide bond; a β-strand; the c-type lectin domain

Full CLEC6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC6A p.Ala81Pro Uncertain significance ★ ⚠ same type
CLEC6A p.Asn146Asp Uncertain significance ★ ⚠ same type
CLEC6A p.Asn160Ser Uncertain significance ★ ⚠ same type
CLEC6A p.Asn170Ser Uncertain significance ★ ⚠ same type
CLEC6A p.Asn190Ser Uncertain significance ★ ⚠ same type
CLEC6A p.Glu132Lys Uncertain significance ★ ⚠ same type
CLEC6A p.Glu168Lys Uncertain significance ★ ⚠ same type
CLEC6A p.His61Gln 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/clec6a-p-val192phe (accessed [today's date]).

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