Is C2CD4A p.Pro227Thr (c.679C>A) pathogenic?

C2CD4A p.Pro227Thr (c.679C>A) is classified Uncertain significance in C2CD4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0785); Absent from gnomAD v4.1.

How common is C2CD4A p.Pro227Thr (c.679C>A) in the general population?

C2CD4A p.Pro227Thr (c.679C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C2CD4A p.Pro227Thr (c.679C>A)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

C2CD4A p.Pro227Thr

c.679C>A · VCV3993983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,412,682)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -2.7
Regional constraint	o/e 1.06	unconstrained · MANE · 1,106 bp · p 0.13 · regional, not allelic
Overall
CADD	5.828	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

No allele count reported in gnomAD v4.1 (AN 1,412,682). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: C2CD4A
Protein: p.Pro227Thr
Coding: c.679C>A
MANE Select: NM_207322
Type: single nucleotide variant
Location: chr15:62068292 (GRCh38)
Gene constraint: LOEUF 1.963 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.36
Residue 227: the 'disordered' region

Full C2CD4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4A p.Ala102Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala160Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala192Glu Uncertain significance ★ ⚠ same type
C2CD4A p.Ala226Asp Uncertain significance ★ ⚠ same type
C2CD4A p.Ala318Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala318Val Uncertain significance ★ ⚠ same type
C2CD4A p.Ala338Val Uncertain significance ★ ⚠ same type
C2CD4A p.Arg177Gly 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/c2cd4a-p-pro227thr (accessed [today's date]).

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