Is CLEC7A p.Ser99Phe (c.296C>T) pathogenic?

CLEC7A p.Ser99Phe (c.296C>T) is classified Uncertain significance in CLEC7A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1035); Very rare (popmax 0.00229%, nfe).

How common is CLEC7A p.Ser99Phe (c.296C>T) in the general population?

CLEC7A p.Ser99Phe (c.296C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about CLEC7A p.Ser99Phe (c.296C>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

CLEC7A p.Ser99Phe

c.296C>T · VCV3267708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -7.85	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 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.49 · regional, not allelic
Overall
CADD	24.7	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 0.00229% European (non-Finnish) · 27/1,179,516 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00167% 27/1,612,784 alleles · very rare exomes 25/1,460,622 · genomes 2/152,162 · joint denominator

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: CLEC7A
Protein: p.Ser99Phe
Coding: c.296C>T
MANE Select: NM_197947
Type: single nucleotide variant
Location: chr12:10126615 (GRCh38)
Gene constraint: LOEUF 1.453 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90

Full CLEC7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC7A c.*2A>G Benign ★★ same type
CLEC7A p.Ile223Ser Benign ★★ ⚠ same type
CLEC7A p.Leu133= Benign/Likely benign ★★ same type
CLEC7A p.Leu183Phe Benign/Likely benign ★★ ⚠ same type
CLEC7A p.Ser161Leu Benign ★★ same type
CLEC7A p.Tyr238Ter Benign/Likely benign ★★ same type
CLEC7A p.Val63= Likely benign ★★ same type
CLEC7A p.Arg185Gln 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/clec7a-p-ser99phe (accessed [today's date]).

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