Is C2CD4D p.Leu43Phe (c.127C>T) pathogenic?

C2CD4D p.Leu43Phe (c.127C>T) is classified Uncertain significance in C2CD4D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: ambiguous (0.5212); Very rare (popmax 0.00841%, afr).

How common is C2CD4D p.Leu43Phe (c.127C>T) in the general population?

C2CD4D p.Leu43Phe (c.127C>T) is very rare (popmax 0.00841%, afr) (gnomAD).

What do computational predictors say about C2CD4D p.Leu43Phe (c.127C>T)?

AlphaMissense predicts ambiguous (score 0.5212) — an in-silico prediction, not a clinical call.

C2CD4D p.Leu43Phe

c.127C>T · VCV3994013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00841%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5212	ambiguous
REVEL	0.169	moderately benign-leaning
SaProt	LLR -8.16	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Overall
CADD	25.2	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 0.00841% African / African-American · 6/71,342 alleles

Filtering AF 0.00361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00248%

Overall 0.00163% 25/1,537,948 alleles · very rare exomes 18/1,386,000 · genomes 7/151,948 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00841%	11,890
Admixed American	0.00403%	24,795
European (non-Finnish)	0.00149%	67,128

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.Leu43Phe
Coding: c.127C>T
MANE Select: NM_001394591
Type: single nucleotide variant
Location: chr1:151838863 (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.Arg102Trp Uncertain significance ★ ⚠ same type
C2CD4D p.Arg185His 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-leu43phe (accessed [today's date]).

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