Is CD2AP p.Arg74Thr (c.221G>C) pathogenic?

CD2AP p.Arg74Thr (c.221G>C) is classified Uncertain significance in CD2AP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: ambiguous (0.3979); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CD2AP p.Arg74Thr (c.221G>C)?

CD2AP p.Arg74Thr (c.221G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CD2AP p.Arg74Thr (c.221G>C) in the general population?

CD2AP p.Arg74Thr (c.221G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD2AP p.Arg74Thr (c.221G>C)?

AlphaMissense predicts ambiguous (score 0.3979) — an in-silico prediction, not a clinical call.

CD2AP p.Arg74Thr

c.221G>C · rs758523796 · VCV2621918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3979	ambiguous
REVEL	0.053	moderately benign-leaning
SaProt	LLR -5.85	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 7.3	GERP 1.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 146 kb · p 0.14 · regional, not allelic
Overall
CADD	23.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CD2AP
Protein: p.Arg74Thr
Coding: c.221G>C
MANE Select: NM_012120
dbSNP: rs758523796
Type: single nucleotide variant
Location: chr6:47533657 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.04 · 12 PDB
Residue 74: the 'interaction with anln and localization to the midbody' region

Full CD2AP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD2AP p.Arg74Met Uncertain significance ★★ ⚠ same residue
CD2AP p.Arg228Gln Uncertain significance ★★ ⚠ same condition
CD2AP p.Arg504Cys Uncertain significance ★★ same condition
CD2AP p.Arg84Gln Uncertain significance ★★ ⚠ same condition
CD2AP p.Asn427Ser Uncertain significance ★★ ⚠ same condition
CD2AP p.Asn506Ser Uncertain significance ★★ ⚠ same condition
CD2AP p.Asp473Gly Uncertain significance ★★ ⚠ same condition
CD2AP p.Gly605Arg Uncertain significance ★★ ⚠ same condition

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/cd2ap-p-arg74thr (accessed [today's date]).

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