Is C2 p.Leu357= (c.1071C>T) pathogenic?

C2 p.Leu357= (c.1071C>T) is classified Likely benign in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). Very rare (popmax 0.00893%, eas).

How common is C2 p.Leu357= (c.1071C>T) in the general population?

C2 p.Leu357= (c.1071C>T) is very rare (popmax 0.00893%, eas) (gnomAD).

C2 p.Leu357=

c.1071C>T · VCV3617435

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00893%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.015	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -16	GERP -3.5
Overall
CADD	0.028	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00893% East Asian · 4/44,800 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000558% 9/1,612,598 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00893%	11,200
Admixed American	0.00334%	29,982
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	0.000169%	589,984

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: C2
Protein: p.Leu357=
Coding: c.1071C>T
MANE Select: NM_000063
Type: single nucleotide variant
Location: chr6:31937401 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 357: the vwfa domain; an α-helix

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/c2-p-leu357 (accessed [today's date]).

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