Is CD2AP p.His174Pro (c.521A>C) pathogenic?

CD2AP p.His174Pro (c.521A>C) is classified Uncertain significance in CD2AP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.0544); Ultra-rare (popmax 0.025%, amr); Associated with Inborn genetic diseases.

What condition is associated with CD2AP p.His174Pro (c.521A>C)?

CD2AP p.His174Pro (c.521A>C) is associated with Inborn genetic diseases, focal segmental glomerulosclerosis 3, susceptibility to (ClinVar).

How common is CD2AP p.His174Pro (c.521A>C) in the general population?

CD2AP p.His174Pro (c.521A>C) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about CD2AP p.His174Pro (c.521A>C)?

AlphaMissense predicts likely benign (score 0.0544) — an in-silico prediction, not a clinical call.

CD2AP p.His174Pro

c.521A>C · rs762020246 · VCV1017628

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0544 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0544	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -4.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -2.9, phastCons 0.95
Regional constraint	o/e 1.05	unconstrained · MANE · 146 kb · p 0.14 · regional, not allelic
Overall
CADD	11.17	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

Grpmax group 0.025% Admixed American · 15/59,980 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00105% 17/1,613,408 alleles · ultra-rare exomes 15/1,461,192 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,999
African / African-American	0.00133%	74,920
European (non-Finnish)	8.48e-05%	1,179,628

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.His174Pro
Coding: c.521A>C
MANE Select: NM_012120
dbSNP: rs762020246
Type: single nucleotide variant
Location: chr6:47554746 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.04 · 12 PDB
Residue 174: the 'interaction with anln and localization to the midbody' region; the 'disordered' 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

Also linked: focal segmental glomerulosclerosis 3, susceptibility to

Similar variants

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
CD2AP c.*496A>G 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-his174pro (accessed [today's date]).

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