Is C2CD2L p.Glu306Lys (c.916G>A) pathogenic?

C2CD2L p.Glu306Lys (c.916G>A) is classified Uncertain significance in C2CD2L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely benign (0.0872); Ultra-rare (popmax 0.015%, amr).

How common is C2CD2L p.Glu306Lys (c.916G>A) in the general population?

C2CD2L p.Glu306Lys (c.916G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about C2CD2L p.Glu306Lys (c.916G>A)?

AlphaMissense predicts likely benign (score 0.0872) — an in-silico prediction, not a clinical call.

C2CD2L p.Glu306Lys

c.916G>A · VCV3483494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0872	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.7	GERP 0.95, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,511 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	22.1	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 0.015% Admixed American · 9/60,004 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000744% 12/1,613,914 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
South Asian	0.0011%	91,070
European (non-Finnish)	0.00017%	589,971

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: C2CD2L
Protein: p.Glu306Lys
Coding: c.916G>A
MANE Select: NM_001290474
Type: single nucleotide variant
Location: chr11:119111526 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 64.75 · 1 PDB
Residue 306: the c2 domain

Full C2CD2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD2L c.451-8G>A Benign ★★ same type
C2CD2L p.Ala14Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala173Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala245Ser Uncertain significance ★ ⚠ same type
C2CD2L p.Ala245Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala326Val Uncertain significance ★ ⚠ same type
C2CD2L p.Ala512Val Uncertain significance ★ ⚠ same type
C2CD2L p.Ala524Thr 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/c2cd2l-p-glu306lys (accessed [today's date]).

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