Is C2 p.Arg124Trp (c.370C>T) pathogenic?

C2 p.Arg124Trp (c.370C>T) is classified Uncertain significance in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-01). AlphaMissense: likely benign (0.1171); Very rare (popmax 0.004%, afr).

How common is C2 p.Arg124Trp (c.370C>T) in the general population?

C2 p.Arg124Trp (c.370C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about C2 p.Arg124Trp (c.370C>T)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

C2 p.Arg124Trp

c.370C>T · rs200459401 · VCV1521890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign
REVEL	0.423	indeterminate
SaProt	LLR -10.24	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.79, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	26.3	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 0.004% African / African-American · 3/75,056 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.00031% 5/1,614,194 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,019
Finnishnot grpmax-eligible	0.00156%	64,028
South Asian	0.0011%	91,086

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.Arg124Trp
Coding: c.370C>T
MANE Select: NM_000063
dbSNP: rs200459401
Type: single nucleotide variant
Location: chr6:31928845 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 124: a disulfide bond; the sushi 2 domain; a β-strand

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

Similar variants

C2 p.Arg124Gln Uncertain significance ★★ ⚠ same residue
C2 p.Arg124= 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.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-arg124trp (accessed [today's date]).

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