Is C2CD4B p.Leu196Pro (c.587T>C) pathogenic?

C2CD4B p.Leu196Pro (c.587T>C) is classified Uncertain significance in C2CD4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.063); Very rare (popmax 0.00449%, nfe).

How common is C2CD4B p.Leu196Pro (c.587T>C) in the general population?

C2CD4B p.Leu196Pro (c.587T>C) is very rare (popmax 0.00449%, nfe) (gnomAD).

What do computational predictors say about C2CD4B p.Leu196Pro (c.587T>C)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

C2CD4B p.Leu196Pro

c.587T>C · rs903065850 · VCV2518729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.063	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56	GERP -2.3
Regional constraint	o/e 1.11	unconstrained · MANE · 1,091 bp · p 0.0058 · regional, not allelic
Overall
CADD	8.975	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 0.00449% European (non-Finnish) · 49/1,092,102 alleles

Filtering AF 0.00343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.0036% 51/1,418,216 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00449%	22,288
Remaining individualsnot grpmax-eligible	0.00368%	27,183

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.Leu196Pro
Coding: c.587T>C
MANE Select: NM_001007595
dbSNP: rs903065850
Type: single nucleotide variant
Location: chr15:62164398 (GRCh38)
Structure: AlphaFold pLDDT 60.81
Residue 196: the 'disordered' region

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-leu196pro (accessed [today's date]).

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