Is C2CD4C p.Arg185Trp (c.553C>T) pathogenic?

C2CD4C p.Arg185Trp (c.553C>T) is classified Uncertain significance in C2CD4C (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.136); Ultra-rare (popmax 0.0103%, amr).

How common is C2CD4C p.Arg185Trp (c.553C>T) in the general population?

C2CD4C p.Arg185Trp (c.553C>T) is ultra-rare (popmax 0.0103%, amr) (gnomAD).

What do computational predictors say about C2CD4C p.Arg185Trp (c.553C>T)?

AlphaMissense predicts likely benign (score 0.136) — an in-silico prediction, not a clinical call.

C2CD4C p.Arg185Trp

c.553C>T · rs760182736 · VCV2207450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.136	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -9.54	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 1.7	GERP 0.59, phastCons 0.37
Regional constraint	o/e 1.07	unconstrained · MANE · 1,262 bp · p 0.088 · regional, not allelic
Overall
CADD	22.6	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 0.0103% Admixed American · 5/48,456 alleles

Filtering AF 0.00398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00259%

Overall 0.00111% 17/1,535,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0103%	9,691
African / African-American	0.00418%	23,911
Remaining individualsnot grpmax-eligible	0.00169%	59,258
South Asian	0.00121%	82,804
European (non-Finnish)	0.000614%	162,905

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: C2CD4C
Protein: p.Arg185Trp
Coding: c.553C>T
MANE Select: NM_001136263
dbSNP: rs760182736
Type: single nucleotide variant
Location: chr19:407809 (GRCh38)
Gene constraint: LOEUF 1.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88
Residue 185: the 'disordered' region

Full C2CD4C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4C p.Arg185Gly Uncertain significance ★ ⚠ same residue
C2CD4C p.Ala107Thr Uncertain significance ★ ⚠ same type
C2CD4C p.Ala151Ser Uncertain significance ★ ⚠ same type
C2CD4C p.Ala154Ser Uncertain significance ★ ⚠ same type
C2CD4C p.Ala181Pro Uncertain significance ★ ⚠ same type
C2CD4C p.Ala187Val Uncertain significance ★ ⚠ same type
C2CD4C p.Ala203Val Uncertain significance ★ ⚠ same type
C2CD4C p.Ala248Thr 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/c2cd4c-p-arg185trp (accessed [today's date]).

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