Is C2CD3 p.Phe910Leu (c.2728T>C) pathogenic?

C2CD3 p.Phe910Leu (c.2728T>C) is classified Uncertain significance in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-27). AlphaMissense: likely pathogenic (0.9805); Very rare (popmax 0.00161%, nfe).

How common is C2CD3 p.Phe910Leu (c.2728T>C) in the general population?

C2CD3 p.Phe910Leu (c.2728T>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about C2CD3 p.Phe910Leu (c.2728T>C)?

AlphaMissense predicts likely pathogenic (score 0.9805) — an in-silico prediction, not a clinical call.

C2CD3 p.Phe910Leu

c.2728T>C · rs1275947843 · VCV1315115

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9805	likely pathogenic · top 2% in C2CD3
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -1.98	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	27.3	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 0.00161% European (non-Finnish) · 19/1,178,392 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00137% 20/1,456,100 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,021
Remaining individualsnot grpmax-eligible	0.00161%	62,268

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: C2CD3
Protein: p.Phe910Leu
Coding: c.2728T>C
MANE Select: NM_001286577
dbSNP: rs1275947843
Type: single nucleotide variant
Location: chr11:74100529 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 910: the c2 2 domain

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ same type
C2CD3 c.4951+6C>T Uncertain significance ★★ same type
C2CD3 c.5495+4A>G 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/c2cd3-p-phe910leu (accessed [today's date]).

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