Is C2CD5 p.His14Asp (c.40C>G) pathogenic?

C2CD5 p.His14Asp (c.40C>G) is classified Uncertain significance in C2CD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.6077); Very rare (popmax 0.000508%, nfe).

How common is C2CD5 p.His14Asp (c.40C>G) in the general population?

C2CD5 p.His14Asp (c.40C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about C2CD5 p.His14Asp (c.40C>G)?

AlphaMissense predicts likely pathogenic (score 0.6077) — an in-silico prediction, not a clinical call.

C2CD5 p.His14Asp

c.40C>G · VCV3483576

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6077 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6077	likely pathogenic
REVEL	0.195	benign-leaning
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 18 kb · p 3.5e-12 · regional, not allelic
Overall
CADD	26.5	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 0.000508% European (non-Finnish) · 6/1,179,978 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,818 alleles · very rare

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: C2CD5
Protein: p.His14Asp
Coding: c.40C>G
MANE Select: NM_001286176
Type: single nucleotide variant
Location: chr12:22544111 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.34
Residue 14: the c2 domain

Full C2CD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD5 p.Ala21Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala242Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala252Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala342Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala355Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala405Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala433Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala527Thr 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/c2cd5-p-his14asp (accessed [today's date]).

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