Is C2CD5 p.Ile196Val (c.586A>G) pathogenic?

C2CD5 p.Ile196Val (c.586A>G) is classified Uncertain significance in C2CD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.4693); Very rare (popmax 8.48e-05%, nfe).

How common is C2CD5 p.Ile196Val (c.586A>G) in the general population?

C2CD5 p.Ile196Val (c.586A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about C2CD5 p.Ile196Val (c.586A>G)?

AlphaMissense predicts ambiguous (score 0.4693) — an in-silico prediction, not a clinical call.

C2CD5 p.Ile196Val

c.586A>G · VCV4217331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4693	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -8.24	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 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 988 bp · p 4.8e-05 · regional, not allelic
Overall
CADD	23.6	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 8.48e-05% European (non-Finnish) · 1/1,179,722 alleles

Overall 6.84e-05% 1/1,461,114 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.Ile196Val
Coding: c.586A>G
MANE Select: NM_001286176
Type: single nucleotide variant
Location: chr12:22524487 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.34

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-ile196val (accessed [today's date]).

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