Is C2 p.Ala370Val (c.1109C>T) pathogenic?

C2 p.Ala370Val (c.1109C>T) is classified Conflicting classifications of pathogenicity in C2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-24). AlphaMissense: likely benign (0.096); Ultra-rare (popmax 0.0238%, nfe); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Ala370Val (c.1109C>T)?

C2 p.Ala370Val (c.1109C>T) is associated with complement component 2 deficiency, age related macular degeneration 14 (ClinVar).

How common is C2 p.Ala370Val (c.1109C>T) in the general population?

C2 p.Ala370Val (c.1109C>T) is ultra-rare (popmax 0.0238%, nfe) (gnomAD).

What do computational predictors say about C2 p.Ala370Val (c.1109C>T)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

C2 p.Ala370Val

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.1109C>T · rs777200072 · VCV905442

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0238%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	18.04	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 0.0238% European (non-Finnish) · 281/1,179,970 alleles

Filtering AF 0.0215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0206%

Overall 0.0177% 286/1,612,642 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0238%	4,199
Remaining individualsnot grpmax-eligible	0.0032%	31,237
African / African-American	0.00267%	37,419
Finnishnot grpmax-eligible	0.00159%	62,886

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.Ala370Val
Coding: c.1109C>T
MANE Select: NM_000063
dbSNP: rs777200072
Type: single nucleotide variant
Location: chr6:31937439 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 370: the vwfa domain; a β-strand

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

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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-ala370val (accessed [today's date]).

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