Is C2CD6 p.Leu412Pro (c.1235T>C) pathogenic?

C2CD6 p.Leu412Pro (c.1235T>C) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.2421); Very rare (popmax 0.00337%, amr).

How common is C2CD6 p.Leu412Pro (c.1235T>C) in the general population?

C2CD6 p.Leu412Pro (c.1235T>C) is very rare (popmax 0.00337%, amr) (gnomAD).

What do computational predictors say about C2CD6 p.Leu412Pro (c.1235T>C)?

AlphaMissense predicts likely benign (score 0.2421) — an in-silico prediction, not a clinical call.

C2CD6 p.Leu412Pro

c.1235T>C · rs868437955 · VCV3135923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00337%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2421	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -7.26	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 0.23	GERP 0.88
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	5.0	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 0.00337% Admixed American · 2/59,304 alleles

Filtering AF 0.000559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000187% 3/1,604,968 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00337%	29,652
Remaining individualsnot grpmax-eligible	0.00161%	62,096

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: C2CD6
Protein: p.Leu412Pro
Coding: c.1235T>C
MANE Select: NM_001168221
dbSNP: rs868437955
Type: single nucleotide variant
Location: chr2:201536292 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 39.82
Residue 412: the 'disordered' region

Full C2CD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD6 p.Ala1682Thr Uncertain significance ★ same type
C2CD6 p.Ala427Gly Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Pro Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Ser Uncertain significance ★ ⚠ same type
C2CD6 p.Ala646Ser Uncertain significance ★ same type
C2CD6 p.Ala827Asp Uncertain significance ★ same type
C2CD6 p.Arg1134Cys Uncertain significance ★ same type
C2CD6 p.Arg1134His 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/c2cd6-p-leu412pro (accessed [today's date]).

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