Is C2 p.Ala472Thr (c.1414G>A) pathogenic?

C2 p.Ala472Thr (c.1414G>A) is classified Likely benign in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-18). AlphaMissense: ambiguous (0.411); Rare (popmax 0.219%, afr); Associated with age related macular degeneration 14.

What condition is associated with C2 p.Ala472Thr (c.1414G>A)?

C2 p.Ala472Thr (c.1414G>A) is associated with age related macular degeneration 14 (ClinVar).

How common is C2 p.Ala472Thr (c.1414G>A) in the general population?

C2 p.Ala472Thr (c.1414G>A) is rare (popmax 0.219%, afr) (gnomAD).

What do computational predictors say about C2 p.Ala472Thr (c.1414G>A)?

AlphaMissense predicts ambiguous (score 0.411) — an in-silico prediction, not a clinical call.

C2 p.Ala472Thr

c.1414G>A · rs142243595 · VCV356249

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.411 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.219%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

age related macular degeneration 14

Computational evidence

Protein change
AlphaMissense	0.411	ambiguous
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.67	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	27.1	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 0.219% African / African-American · 164/75,030 alleles

Filtering AF 0.191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.0363% 585/1,613,028 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.219%	458
East Asian	0.0668%	1,496
Admixed American	0.0433%	2,309
European (non-Finnish)	0.029%	3,450
Remaining individualsnot grpmax-eligible	0.0272%	3,676
South Asian	0.00659%	15,181

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.Ala472Thr
Coding: c.1414G>A
MANE Select: NM_000063
dbSNP: rs142243595
Type: single nucleotide variant
Location: chr6:31943278 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 472: a disulfide bond; the peptidase s1 domain; a β-strand

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

Disease context

age related macular degeneration 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2 c.1902+5G>A Uncertain significance ★★ same condition
C2 p.Arg129His Uncertain significance ★★ ⚠ same condition
C2 p.Arg734Leu Uncertain significance ★★ ⚠ same condition
C2 p.Asp390Ala Uncertain significance ★★ ⚠ same condition
C2 p.Asp661Asn Uncertain significance ★★ ⚠ same condition
C2 p.Lys572Asn Uncertain significance ★★ ⚠ same condition
C2 p.Phe273= Uncertain significance ★★ same condition
C2 p.Phe95Val 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/c2-p-ala472thr (accessed [today's date]).

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