Is CLEC12A p.Ser259Phe (c.776C>T) pathogenic?

CLEC12A p.Ser259Phe (c.776C>T) is classified Likely benign in CLEC12A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.1222); Very rare (popmax 0.000528%, nfe).

How common is CLEC12A p.Ser259Phe (c.776C>T) in the general population?

CLEC12A p.Ser259Phe (c.776C>T) is very rare (popmax 0.000528%, nfe) (gnomAD).

What do computational predictors say about CLEC12A p.Ser259Phe (c.776C>T)?

AlphaMissense predicts likely benign (score 0.1222) — an in-silico prediction, not a clinical call.

CLEC12A p.Ser259Phe

c.776C>T · VCV3493490

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1222 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000528%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1222	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -7.50	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 -2	GERP -0.38
Regional constraint	o/e 1.12	unconstrained · MANE · 13 kb · p 0.036 · regional, not allelic
Overall
CADD	0.408	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 0.000528% European (non-Finnish) · 6/1,136,920 alleles

Filtering AF 0.00019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000125%

Overall 0.000393% 6/1,528,034 alleles · very rare exomes 6/1,376,008 · genomes 0/152,026 · 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: CLEC12A
Protein: p.Ser259Phe
Coding: c.776C>T
MANE Select: NM_138337
Type: single nucleotide variant
Location: chr12:9985004 (GRCh38)
Gene constraint: LOEUF 1.366 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.35 · 3 PDB

Full CLEC12A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC12A c.-3T>C Uncertain significance ★ same type
CLEC12A p.Ala163Thr Uncertain significance ★ ⚠ same type
CLEC12A p.Ala166Asp Uncertain significance ★ ⚠ same type
CLEC12A p.Ala166Val Uncertain significance ★ ⚠ same type
CLEC12A p.Ala176Ser Uncertain significance ★ ⚠ same type
CLEC12A p.Arg119Cys Uncertain significance ★ ⚠ same type
CLEC12A p.Asn101Ser Uncertain significance ★ ⚠ same type
CLEC12A p.Asn105Lys 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/clec12a-p-ser259phe (accessed [today's date]).

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