Is C2CD4D p.Pro98Gln (c.293C>A) pathogenic?

C2CD4D p.Pro98Gln (c.293C>A) is classified Uncertain significance in C2CD4D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely pathogenic (0.8097); Ultra-rare (popmax 0.0171%, sas).

How common is C2CD4D p.Pro98Gln (c.293C>A) in the general population?

C2CD4D p.Pro98Gln (c.293C>A) is ultra-rare (popmax 0.0171%, sas) (gnomAD).

What do computational predictors say about C2CD4D p.Pro98Gln (c.293C>A)?

AlphaMissense predicts likely pathogenic (score 0.8097) — an in-silico prediction, not a clinical call.

C2CD4D p.Pro98Gln

c.293C>A · VCV3483571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8097	likely pathogenic · top 6% in C2CD4D
REVEL	0.624	indeterminate
SaProt	LLR -10.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; 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	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0171% South Asian · 10/58,380 alleles

Filtering AF 0.00923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00698%

Overall 0.000901% 11/1,220,802 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0171%	5,838
Remaining individualsnot grpmax-eligible	0.00193%	51,912

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.Pro98Gln
Coding: c.293C>A
MANE Select: NM_001394591
Type: single nucleotide variant
Location: chr1:151838697 (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-pro98gln (accessed [today's date]).

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