Is CD2AP p.Arg74Met (c.221G>T) pathogenic?

CD2AP p.Arg74Met (c.221G>T) is classified Uncertain significance in CD2AP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-08). AlphaMissense: ambiguous (0.3891); Rare (popmax 0.245%, eas); Associated with focal segmental glomerulosclerosis 3, susceptibility to.

What condition is associated with CD2AP p.Arg74Met (c.221G>T)?

CD2AP p.Arg74Met (c.221G>T) is associated with focal segmental glomerulosclerosis 3, susceptibility to (ClinVar).

How common is CD2AP p.Arg74Met (c.221G>T) in the general population?

CD2AP p.Arg74Met (c.221G>T) is rare (popmax 0.245%, eas) (gnomAD).

What do computational predictors say about CD2AP p.Arg74Met (c.221G>T)?

AlphaMissense predicts ambiguous (score 0.3891) — an in-silico prediction, not a clinical call.

CD2AP p.Arg74Met

c.221G>T · rs758523796 · VCV911543

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3891 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.245%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

focal segmental glomerulosclerosis 3, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.3891	ambiguous
REVEL	0.064	moderately benign-leaning
SaProt	LLR -7.98	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	23.9	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 0.245% East Asian · 110/44,868 alleles

Filtering AF 0.208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.194%

Overall 0.00694% 112/1,614,066 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.245%	408
Remaining individualsnot grpmax-eligible	0.0032%	31,247

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: CD2AP
Protein: p.Arg74Met
Coding: c.221G>T
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

focal segmental glomerulosclerosis 3, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD2AP p.Arg74Thr Uncertain significance ★ ⚠ same residue
CD2AP c.1274+3A>G Uncertain significance ★★ same condition
CD2AP c.1633-6T>A Uncertain significance ★★ same condition
CD2AP c.-130C>G Uncertain significance ★★ same condition
CD2AP c.-166A>G Uncertain significance ★★ same condition
CD2AP c.*319A>C Uncertain significance ★★ same condition
CD2AP c.*452C>G Uncertain significance ★★ same condition
CD2AP c.*494G>A 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-arg74met (accessed [today's date]).

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