Is C2CD4B p.Arg38Leu (c.113G>T) pathogenic?

C2CD4B p.Arg38Leu (c.113G>T) is classified Uncertain significance in C2CD4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely benign (0.234); Ultra-rare (popmax 0.0377%, amr).

How common is C2CD4B p.Arg38Leu (c.113G>T) in the general population?

C2CD4B p.Arg38Leu (c.113G>T) is ultra-rare (popmax 0.0377%, amr) (gnomAD).

What do computational predictors say about C2CD4B p.Arg38Leu (c.113G>T)?

AlphaMissense predicts likely benign (score 0.234) — an in-silico prediction, not a clinical call.

C2CD4B p.Arg38Leu

c.113G>T · rs776480122 · VCV3135885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.234 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0377%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.234	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -4.43	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -0.39, phastCons 0.97
Regional constraint	o/e 1.11	unconstrained · MANE · 1,091 bp · p 0.0058 · regional, not allelic
Overall
CADD	25.8	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 0.0377% Admixed American · 18/47,806 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.00146% 22/1,510,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0377%	2,656
Remaining individualsnot grpmax-eligible	0.00341%	29,313
European (non-Finnish)	0.000176%	567,035

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: C2CD4B
Protein: p.Arg38Leu
Coding: c.113G>T
MANE Select: NM_001007595
dbSNP: rs776480122
Type: single nucleotide variant
Location: chr15:62164872 (GRCh38)
Structure: AlphaFold pLDDT 60.81

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

Similar variants

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
C2CD4B p.Ala244Val 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-arg38leu (accessed [today's date]).

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