Is C2 p.Phe95Val (c.283T>G) pathogenic?

C2 p.Phe95Val (c.283T>G) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-10). AlphaMissense: ambiguous (0.4295); Rare (popmax 0.486%, eas); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Phe95Val (c.283T>G)?

C2 p.Phe95Val (c.283T>G) is associated with complement component 2 deficiency, age related macular degeneration 14 (ClinVar).

How common is C2 p.Phe95Val (c.283T>G) in the general population?

C2 p.Phe95Val (c.283T>G) is rare (popmax 0.486%, eas) (gnomAD).

What do computational predictors say about C2 p.Phe95Val (c.283T>G)?

AlphaMissense predicts ambiguous (score 0.4295) — an in-silico prediction, not a clinical call.

C2 p.Phe95Val

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.283T>G · rs201023669 · VCV905373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4295 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.486%, eas)

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.4295	ambiguous
REVEL	0.401	indeterminate
SaProt	LLR -10.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	26.5	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 0.486% East Asian · 218/44,890 alleles

Filtering AF 0.433% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.412%

Overall 0.0136% 219/1,614,228 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.486%	206
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Phe95Val
Coding: c.283T>G
MANE Select: NM_000063
dbSNP: rs201023669
Type: single nucleotide variant
Location: chr6:31928758 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 95: a disulfide bond; the sushi 2 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 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.Ser250Cys 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-phe95val (accessed [today's date]).

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