Is C2CD4B p.Trp65Arg (c.193T>C) pathogenic?

C2CD4B p.Trp65Arg (c.193T>C) is classified Uncertain significance in C2CD4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: ambiguous (0.4912); Absent from gnomAD v4.1.

How common is C2CD4B p.Trp65Arg (c.193T>C) in the general population?

C2CD4B p.Trp65Arg (c.193T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C2CD4B p.Trp65Arg (c.193T>C)?

AlphaMissense predicts ambiguous (score 0.4912) — an in-silico prediction, not a clinical call.

C2CD4B p.Trp65Arg

c.193T>C · VCV4647253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4912 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4912	ambiguous
REVEL	0.099	moderately benign-leaning
SaProt	LLR -4.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.24, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,091 bp · p 0.0058 · regional, not allelic
Overall
CADD	13.77	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C2CD4B
Protein: p.Trp65Arg
Coding: c.193T>C
MANE Select: NM_001007595
Type: single nucleotide variant
Location: chr15:62164792 (GRCh38)
Structure: AlphaFold pLDDT 60.81

Full C2CD4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4B p.Trp65Cys Uncertain significance ★ ⚠ same residue
C2CD4B p.Ala138Thr Uncertain significance ★ ⚠ same type
C2CD4B p.Ala190Gly Uncertain significance ★ ⚠ same type
C2CD4B p.Ala197Val Uncertain significance ★ ⚠ same type
C2CD4B p.Ala20Asp Uncertain significance ★ ⚠ same type
C2CD4B p.Ala231Pro Uncertain significance ★ ⚠ same type
C2CD4B p.Ala239Val Uncertain significance ★ ⚠ same type
C2CD4B p.Ala244Thr 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/c2cd4b-p-trp65arg (accessed [today's date]).

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