Is C2 p.Arg77Trp (c.229C>T) pathogenic?

C2 p.Arg77Trp (c.229C>T) is classified Uncertain significance in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-24). AlphaMissense: likely benign (0.117); Very rare (popmax 0.00667%, afr).

How common is C2 p.Arg77Trp (c.229C>T) in the general population?

C2 p.Arg77Trp (c.229C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about C2 p.Arg77Trp (c.229C>T)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

C2 p.Arg77Trp

c.229C>T · rs768231128 · VCV1373059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.096	GERP -0.72
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,916 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00105% 17/1,611,944 alleles · very rare exomes 15/1,459,726 · genomes 2/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,983
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Remaining individualsnot grpmax-eligible	0.0016%	62,440
South Asian	0.0011%	90,964
European (non-Finnish)	0.000763%	131,097

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.Arg77Trp
Coding: c.229C>T
MANE Select: NM_000063
dbSNP: rs768231128
Type: single nucleotide variant
Location: chr6:31928137 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 77: the sushi 1 domain

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

Similar variants

C2 p.Arg77= Likely benign ★ same residue
C2 c.1902+5G>A Uncertain significance ★★ same type
C2 c.2029+5G>A Uncertain significance ★★ same type
C2 p.Ala363Thr Uncertain significance ★★ ⚠ same type
C2 p.Ala682Glu Uncertain significance ★★ ⚠ same type
C2 p.Arg124Gln Uncertain significance ★★ ⚠ same type
C2 p.Arg129His Uncertain significance ★★ same type
C2 p.Arg174Cys Uncertain significance ★★ ⚠ same type

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-arg77trp (accessed [today's date]).

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