Is C2CD3 p.Phe1050Leu (c.3148T>C) pathogenic?

C2CD3 p.Phe1050Leu (c.3148T>C) is classified Benign/Likely benign in C2CD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). AlphaMissense: ambiguous (0.4527); Low-frequency (popmax 1.19%, afr).

How common is C2CD3 p.Phe1050Leu (c.3148T>C) in the general population?

C2CD3 p.Phe1050Leu (c.3148T>C) is low-frequency (popmax 1.19%, afr) (gnomAD).

What do computational predictors say about C2CD3 p.Phe1050Leu (c.3148T>C)?

AlphaMissense predicts ambiguous (score 0.4527) — an in-silico prediction, not a clinical call.

C2CD3 p.Phe1050Leu

c.3148T>C · rs79373272 · VCV779307

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4527 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.19%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4527	ambiguous
REVEL	0.027	moderately benign-leaning
SaProt	LLR -4.67	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 2.5	GERP -2.1, phastCons 0.88
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	10.8	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 1.19% African / African-American · 888/74,930 alleles

Filtering AF 1.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.09%

Overall 0.0631% 1,016/1,611,386 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.19%	84
Remaining individualsnot grpmax-eligible	0.101%	990
Admixed American	0.087%	1,150
Middle Eastern	0.0662%	1,511
South Asian	0.00331%	30,204
European (non-Finnish)	0.000509%	196,406

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.Phe1050Leu
Coding: c.3148T>C
MANE Select: NM_001286577
dbSNP: rs79373272
Type: single nucleotide variant
Location: chr11:74095240 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1050: the c2 3 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-phe1050leu (accessed [today's date]).

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