Is CLEC7A p.Pro41Leu (c.122C>T) pathogenic?

CLEC7A p.Pro41Leu (c.122C>T) is classified Uncertain significance in CLEC7A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0715); Ultra-rare (popmax 0.0799%, sas).

How common is CLEC7A p.Pro41Leu (c.122C>T) in the general population?

CLEC7A p.Pro41Leu (c.122C>T) is ultra-rare (popmax 0.0799%, sas) (gnomAD).

What do computational predictors say about CLEC7A p.Pro41Leu (c.122C>T)?

AlphaMissense predicts likely benign (score 0.0715) — an in-silico prediction, not a clinical call.

CLEC7A p.Pro41Leu

c.122C>T · rs150877695 · VCV2599501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0799%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0715	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.37	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 0.45	GERP -3.8, phastCons 0.15
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.49 · regional, not allelic
Overall
CADD	7.343	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 0.0799% South Asian · 68/85,060 alleles

Filtering AF 0.0647% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00729% 114/1,564,334 alleles · ultra-rare exomes 107/1,412,230 · genomes 7/152,104 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0799%	1,251
Middle Eastern	0.05%	2,002
Remaining individualsnot grpmax-eligible	0.0181%	5,526
European (non-Finnish)	0.00277%	36,042

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.Pro41Leu
Coding: c.122C>T
MANE Select: NM_197947
dbSNP: rs150877695
Type: single nucleotide variant
Location: chr12:10127827 (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 p.Pro41Ala Uncertain significance ★ ⚠ same residue
CLEC7A p.Pro41Thr Uncertain significance ★ ⚠ same residue
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

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-pro41leu (accessed [today's date]).

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