Is C2 p.Glu318Asp (c.954G>C) pathogenic?

C2 p.Glu318Asp (c.954G>C) is classified Benign/Likely benign in C2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1629); Common (popmax 5.23%, sas) — too common for a highly-penetrant pathogenic allele; Associated with complement component 2 deficiency.

What condition is associated with C2 p.Glu318Asp (c.954G>C)?

C2 p.Glu318Asp (c.954G>C) is associated with complement component 2 deficiency, age related macular degeneration 14 (ClinVar).

What do computational predictors say about C2 p.Glu318Asp (c.954G>C)?

AlphaMissense predicts likely benign (score 0.1629) — an in-silico prediction, not a clinical call.

C2 p.Glu318Asp

Q: How common is C2 p.Glu318Asp (c.954G>C) in the general population?

C2 p.Glu318Asp (c.954G>C) is common (popmax 5.23%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.954G>C · rs9332739 · VCV12130

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1629 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.23%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.1629	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	12.59	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 5.23% South Asian · 4,761/91,076 alleles

Filtering AF 5.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.05%

Overall 4.2% 67,705/1,612,940 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	5.49%	18
South Asiangrpmax	5.23%	19
European (non-Finnish)	4.48%	22
Remaining individualsnot grpmax-eligible	3.79%	26
Middle Eastern	2.74%	37
Ashkenazi Jewishnot grpmax-eligible	2.56%	39
Admixed American	2.32%	43
East Asian	2.22%	45
Amishnot grpmax-eligible	1.32%	76
African / African-American	1.2%	83

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu318Asp
Coding: c.954G>C
MANE Select: NM_000063
dbSNP: rs9332739
Type: single nucleotide variant
Location: chr6:31936027 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 318: a UniProt-annotated variant site (may be associated with a reduced risk for age-related macular degeneration); the vwfa domain; an α-helix

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.Glu318= 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-glu318asp (accessed [today's date]).

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