Is DAAM2 p.Pro74Thr (c.220C>A) pathogenic?

DAAM2 p.Pro74Thr (c.220C>A) is classified Uncertain significance in DAAM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0927); Ultra-rare (popmax 0.0647%, eas); Associated with nephrotic syndrome, type 24.

What condition is associated with DAAM2 p.Pro74Thr (c.220C>A)?

DAAM2 p.Pro74Thr (c.220C>A) is associated with nephrotic syndrome, type 24 (ClinVar).

How common is DAAM2 p.Pro74Thr (c.220C>A) in the general population?

DAAM2 p.Pro74Thr (c.220C>A) is ultra-rare (popmax 0.0647%, eas) (gnomAD).

What do computational predictors say about DAAM2 p.Pro74Thr (c.220C>A)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

DAAM2 p.Pro74Thr

c.220C>A · rs370112679 · VCV2582327

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0647%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 24

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -8.07	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 4.9	GERP 0.19, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 8,771 bp · p 0.57 · regional, not allelic
Overall
CADD	22.7	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 0.0647% East Asian · 29/44,842 alleles

Filtering AF 0.0462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00589% 95/1,613,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0647%	1,546
Remaining individualsnot grpmax-eligible	0.0576%	1,735
South Asian	0.0298%	3,357
Admixed American	0.00334%	29,964
European (non-Finnish)	8.48e-05%	1,179,642

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: DAAM2
Protein: p.Pro74Thr
Coding: c.220C>A
MANE Select: NM_001201427
dbSNP: rs370112679
Type: single nucleotide variant
Location: chr6:39860979 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 80.02
Residue 74: the gbd/fh3 domain

Full DAAM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrotic syndrome, type 24 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DAAM2 p.Arg335Trp Uncertain significance ★★ ⚠ same condition
DAAM2 p.Arg676Trp Uncertain significance ★★ ⚠ same condition
DAAM2 p.Arg990Cys Uncertain significance ★★ ⚠ same condition
DAAM2 p.Gln760Arg Uncertain significance ★★ ⚠ same condition
DAAM2 p.Arg66Ter Likely pathogenic ★ same condition
DAAM2 p.Gly1020Ter Likely pathogenic ★ same condition
DAAM2 p.Glu735Lys Uncertain significance ★ ⚠ same condition
DAAM2 p.Pro582His Conflicting classifications of pathogenicity ★ ⚠ 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/daam2-p-pro74thr (accessed [today's date]).

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