Is C2CD4D p.Arg102Trp (c.304C>T) pathogenic?

C2CD4D p.Arg102Trp (c.304C>T) is classified Uncertain significance in C2CD4D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.6308); Very rare (popmax 0.00304%, amr).

How common is C2CD4D p.Arg102Trp (c.304C>T) in the general population?

C2CD4D p.Arg102Trp (c.304C>T) is very rare (popmax 0.00304%, amr) (gnomAD).

What do computational predictors say about C2CD4D p.Arg102Trp (c.304C>T)?

AlphaMissense predicts likely pathogenic (score 0.6308) — an in-silico prediction, not a clinical call.

C2CD4D p.Arg102Trp

c.304C>T · VCV3994020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6308 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00304%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6308	likely pathogenic
REVEL	0.438	indeterminate
SaProt	LLR -10.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00304% Admixed American · 1/32,916 alleles

Filtering AF 7.5e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.000409% 5/1,221,568 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00304%	32,916
Remaining individualsnot grpmax-eligible	0.00192%	52,026
European (non-Finnish)	0.000282%	354,907

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: C2CD4D
Protein: p.Arg102Trp
Coding: c.304C>T
MANE Select: NM_001394591
Type: single nucleotide variant
Location: chr1:151838686 (GRCh38)
Gene constraint: LOEUF 1.931 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 66.41

Full C2CD4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4D p.Ala120Val Uncertain significance ★ ⚠ same type
C2CD4D p.Ala301Gly Uncertain significance ★ ⚠ same type
C2CD4D p.Ala31Ser Uncertain significance ★ ⚠ same type
C2CD4D p.Ala38Pro Uncertain significance ★ ⚠ same type
C2CD4D p.Ala63Glu Uncertain significance ★ ⚠ same type
C2CD4D p.Ala78Thr Uncertain significance ★ ⚠ same type
C2CD4D p.Arg185His Uncertain significance ★ ⚠ same type
C2CD4D p.Arg185Ser 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/c2cd4d-p-arg102trp (accessed [today's date]).

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