Is C2 p.Ala82Val (c.245C>T) pathogenic?

C2 p.Ala82Val (c.245C>T) is classified Conflicting classifications of pathogenicity in C2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-18). AlphaMissense: likely benign (0.184); Ultra-rare (popmax 0.0329%, mid); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Ala82Val (c.245C>T)?

C2 p.Ala82Val (c.245C>T) is associated with complement component 2 deficiency, age related macular degeneration 14 (ClinVar).

How common is C2 p.Ala82Val (c.245C>T) in the general population?

C2 p.Ala82Val (c.245C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about C2 p.Ala82Val (c.245C>T)?

AlphaMissense predicts likely benign (score 0.184) — an in-silico prediction, not a clinical call.

C2 p.Ala82Val

Q: How is Immunodeficiency due to a classical component pathway complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.245C>T · rs547881286 · VCV905372

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.184	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.41	donor gain · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	24.8	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00398% 64/1,608,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.00772%	12,956
European (non-Finnish)	0.00458%	21,842
Remaining individualsnot grpmax-eligible	0.0016%	62,418

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.Ala82Val
Coding: c.245C>T
MANE Select: NM_000063
dbSNP: rs547881286
Type: single nucleotide variant
Location: chr6:31928153 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 82: a disulfide bond; the sushi 1 domain

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

Disease context

complement component 2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 14

For Immunodeficiency due to a classical component pathway complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C2 p.Ala82= Likely benign ★ same residue
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

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-ala82val (accessed [today's date]).

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