Is C3 p.Val253Ala (c.758T>C) pathogenic?

C3 p.Val253Ala (c.758T>C) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.6668); Very rare (popmax 0.00901%, eas); Associated with Inborn genetic diseases.

What condition is associated with C3 p.Val253Ala (c.758T>C)?

C3 p.Val253Ala (c.758T>C) is associated with Inborn genetic diseases (ClinVar).

How common is C3 p.Val253Ala (c.758T>C) in the general population?

C3 p.Val253Ala (c.758T>C) is very rare (popmax 0.00901%, eas) (gnomAD).

What do computational predictors say about C3 p.Val253Ala (c.758T>C)?

AlphaMissense predicts likely pathogenic (score 0.6668) — an in-silico prediction, not a clinical call.

C3 p.Val253Ala

c.758T>C · rs781713336 · VCV2514800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00901%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6668	likely pathogenic
REVEL	0.327	indeterminate
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	23.1	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 0.00901% East Asian · 4/44,414 alleles

Filtering AF 0.003% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00181%

Overall 0.000312% 5/1,600,954 alleles · very rare exomes 5/1,457,974 · genomes 0/142,980 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00901%	11,103
European (non-Finnish)	8.51e-05%	1,175,750

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.Val253Ala
Coding: c.758T>C
MANE Select: NM_000064
dbSNP: rs781713336
Type: single nucleotide variant
Location: chr19:6714007 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 253: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C3 p.Ala1214Pro Uncertain significance ★★ ⚠ same condition
C3 p.Ala642Thr Uncertain significance ★★ ⚠ same condition
C3 p.Ala655Thr Uncertain significance ★★ ⚠ same condition
C3 p.Ala719Val Uncertain significance ★★ ⚠ same condition
C3 p.Arg1254His Uncertain significance ★★ ⚠ same condition
C3 p.Arg1393Gln Uncertain significance ★★ ⚠ same condition
C3 p.Arg1427Thr Uncertain significance ★★ ⚠ same condition
C3 p.Arg1441Met Uncertain significance ★★ ⚠ same condition

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-val253ala (accessed [today's date]).

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