Is CLEC4D p.Cys199Phe (c.596G>T) pathogenic?

CLEC4D p.Cys199Phe (c.596G>T) is classified Uncertain significance in CLEC4D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.5871); Ultra-rare (popmax 0.0115%, nfe).

How common is CLEC4D p.Cys199Phe (c.596G>T) in the general population?

CLEC4D p.Cys199Phe (c.596G>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about CLEC4D p.Cys199Phe (c.596G>T)?

AlphaMissense predicts likely pathogenic (score 0.5871) — an in-silico prediction, not a clinical call.

CLEC4D p.Cys199Phe

c.596G>T · rs368418350 · VCV2211727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5871	likely pathogenic · top 8% in CLEC4D
REVEL	0.575	indeterminate
SaProt	LLR -12.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 7,535 bp · p 0.08 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0115% European (non-Finnish) · 136/1,179,628 alleles

Filtering AF 0.00994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00932%

Overall 0.00899% 145/1,613,378 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,807
European (non-Finnish)grpmax	0.0115%	8,674
Admixed American	0.00167%	59,972

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CLEC4D
Protein: p.Cys199Phe
Coding: c.596G>T
MANE Select: NM_080387
dbSNP: rs368418350
Type: single nucleotide variant
Location: chr12:8521219 (GRCh38)
Gene constraint: LOEUF 1.613 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.58 · 2 PDB
Residue 199: a disulfide bond; the c-type lectin domain

Full CLEC4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC4D p.Ser32Gly Benign ★★ same type
CLEC4D p.Ala117Ser Uncertain significance ★ ⚠ same type
CLEC4D p.Ala126Thr Uncertain significance ★ ⚠ same type
CLEC4D p.Ala37Glu Uncertain significance ★ ⚠ same type
CLEC4D p.Ala90Gly Uncertain significance ★ ⚠ same type
CLEC4D p.Arg110Ser Uncertain significance ★ ⚠ same type
CLEC4D p.Arg138Trp Uncertain significance ★ ⚠ same type
CLEC4D p.Arg155Cys 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/clec4d-p-cys199phe (accessed [today's date]).

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