Is C2CD4D p.Ser105Phe (c.314C>T) pathogenic?

C2CD4D p.Ser105Phe (c.314C>T) is classified Uncertain significance in C2CD4D (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely pathogenic (0.8556); Rare (popmax 0.177%, nfe).

How common is C2CD4D p.Ser105Phe (c.314C>T) in the general population?

C2CD4D p.Ser105Phe (c.314C>T) is rare (popmax 0.177%, nfe) (gnomAD).

What do computational predictors say about C2CD4D p.Ser105Phe (c.314C>T)?

AlphaMissense predicts likely pathogenic (score 0.8556) — an in-silico prediction, not a clinical call.

C2CD4D p.Ser105Phe

c.314C>T · rs752964206 · VCV2350472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8556 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.177%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8556	likely pathogenic · top 4% in C2CD4D
REVEL	0.491	indeterminate
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Overall
CADD	28.2	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 0.177% European (non-Finnish) · 1,880/1,065,008 alleles

Filtering AF 0.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.148% 2,038/1,373,624 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.177%	566
Remaining individualsnot grpmax-eligible	0.167%	598
South Asian	0.0495%	2,020
Admixed American	0.0425%	2,352
African / African-American	0.0272%	3,675
Middle Eastern	0.0263%	3,804
Finnishnot grpmax-eligible	0.0178%	5,633
Ashkenazi Jewishnot grpmax-eligible	0.0088%	11,358

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: C2CD4D
Protein: p.Ser105Phe
Coding: c.314C>T
MANE Select: NM_001394591
dbSNP: rs752964206
Type: single nucleotide variant
Location: chr1:151838676 (GRCh38)
Gene constraint: LOEUF 1.931 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 66.41

Full C2CD4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4D p.Ala120Val Uncertain significance ★ ⚠ same type
C2CD4D p.Ala301Gly Uncertain significance ★ ⚠ same type
C2CD4D p.Ala31Ser Uncertain significance ★ ⚠ same type
C2CD4D p.Ala38Pro Uncertain significance ★ ⚠ same type
C2CD4D p.Ala63Glu Uncertain significance ★ ⚠ same type
C2CD4D p.Ala78Thr Uncertain significance ★ ⚠ same type
C2CD4D p.Arg102Trp Uncertain significance ★ ⚠ same type
C2CD4D p.Arg185His 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/c2cd4d-p-ser105phe (accessed [today's date]).

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