Is C3 p.Val901Met (c.2701G>A) pathogenic?

C3 p.Val901Met (c.2701G>A) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-10). AlphaMissense: ambiguous (0.3959); Very rare (popmax 0.0022%, sas).

How common is C3 p.Val901Met (c.2701G>A) in the general population?

C3 p.Val901Met (c.2701G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about C3 p.Val901Met (c.2701G>A)?

AlphaMissense predicts ambiguous (score 0.3959) — an in-silico prediction, not a clinical call.

C3 p.Val901Met

c.2701G>A · rs750656770 · VCV1936580

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
AlphaMissense	0.3959	ambiguous
REVEL	0.305	indeterminate
SaProt	LLR -7.40	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	22.1	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 0.0022% South Asian · 2/91,048 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.00062% 10/1,613,488 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,955
South Asiangrpmax	0.0022%	45,524
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.000424%	235,997

Finnish 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: C3
Protein: p.Val901Met
Coding: c.2701G>A
MANE Select: NM_000064
dbSNP: rs750656770
Type: single nucleotide variant
Location: chr19:6697439 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 901: a β-strand; a disulfide bond

Full C3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C3 p.Val901Ala Uncertain significance ★ ⚠ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same type
C3 c.2863+1G>T Likely pathogenic ★★ same type
C3 c.4030-2A>G Likely pathogenic ★★ same type
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same type
C3 p.Arg764Ter Pathogenic/Likely pathogenic ★★ 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/c3-p-val901met (accessed [today's date]).

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