Is CD2AP p.Leu331His (c.992T>A) pathogenic?

CD2AP p.Leu331His (c.992T>A) is classified Conflicting classifications of pathogenicity in CD2AP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-08). AlphaMissense: likely benign (0.1059); Rare (popmax 0.158%, nfe); Associated with focal segmental glomerulosclerosis 3, susceptibility to.

What condition is associated with CD2AP p.Leu331His (c.992T>A)?

CD2AP p.Leu331His (c.992T>A) is associated with focal segmental glomerulosclerosis 3, susceptibility to (ClinVar).

How common is CD2AP p.Leu331His (c.992T>A) in the general population?

CD2AP p.Leu331His (c.992T>A) is rare (popmax 0.158%, nfe) (gnomAD).

What do computational predictors say about CD2AP p.Leu331His (c.992T>A)?

AlphaMissense predicts likely benign (score 0.1059) — an in-silico prediction, not a clinical call.

CD2AP p.Leu331His

c.992T>A · rs140188898 · VCV357171

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1059 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.158%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 3, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.1059	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -6.45	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 1.7	GERP 0.32, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 146 kb · p 0.14 · regional, not allelic
Overall
CADD	18.28	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 0.158% European (non-Finnish) · 1,840/1,164,900 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.149%

Overall 0.122% 1,953/1,597,642 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.158%	633
Remaining individualsnot grpmax-eligible	0.118%	848
African / African-American	0.0268%	3,737
Admixed American	0.0217%	4,615
Middle Eastern	0.0165%	6,046
Finnishnot grpmax-eligible	0.00625%	16,005
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,500
South Asian	0.0011%	90,796

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.Leu331His
Coding: c.992T>A
MANE Select: NM_012120
dbSNP: rs140188898
Type: single nucleotide variant
Location: chr6:47579473 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.04 · 12 PDB

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 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-leu331his (accessed [today's date]).

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