Is DAAM2 p.Arg335Trp (c.1003C>T) pathogenic?

DAAM2 p.Arg335Trp (c.1003C>T) is classified Uncertain significance in DAAM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.9506); Rare (popmax 0.115%, sas); Associated with Inborn genetic diseases.

What condition is associated with DAAM2 p.Arg335Trp (c.1003C>T)?

DAAM2 p.Arg335Trp (c.1003C>T) is associated with Inborn genetic diseases, nephrotic syndrome, type 24 (ClinVar).

How common is DAAM2 p.Arg335Trp (c.1003C>T) in the general population?

DAAM2 p.Arg335Trp (c.1003C>T) is rare (popmax 0.115%, sas) (gnomAD).

What do computational predictors say about DAAM2 p.Arg335Trp (c.1003C>T)?

AlphaMissense predicts likely pathogenic (score 0.9506) — an in-silico prediction, not a clinical call.

DAAM2 p.Arg335Trp

c.1003C>T · rs371806282 · VCV1705482

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9506 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9506	likely pathogenic
REVEL	0.749	pathogenic-leaning
SaProt	LLR -12.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 11 kb · p 5e-07 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.115% South Asian · 97/84,032 alleles

Filtering AF 0.0968% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0899%

Overall 0.00799% 124/1,551,186 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.115%	866
Remaining individualsnot grpmax-eligible	0.00666%	15,020
African / African-American	0.00274%	36,487
European (non-Finnish)	0.00183%	54,621

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.Arg335Trp
Coding: c.1003C>T
MANE Select: NM_001201427
dbSNP: rs371806282
Type: single nucleotide variant
Location: chr6:39871531 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 80.02
Residue 335: the gbd/fh3 domain; a UniProt-annotated variant site (in nphs24; uncertain significance; affects the regulation of filopodia formation)

Full DAAM2 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: nephrotic syndrome, type 24

Similar variants

DAAM2 p.Arg335Gln Pathogenic same residue
DAAM2 p.Arg676Trp Uncertain significance ★★ ⚠ same condition
DAAM2 p.Arg990Cys Uncertain significance ★★ ⚠ same condition
DAAM2 p.Gln760Arg Uncertain significance ★★ ⚠ same condition
DAAM2 p.Glu956Lys Uncertain significance ★★ ⚠ same condition
DAAM2 p.Ile699Val Uncertain significance ★★ ⚠ same condition
DAAM2 p.Pro74Thr Uncertain significance ★★ ⚠ same condition
DAAM2 p.Arg66Ter Likely pathogenic ★ 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-arg335trp (accessed [today's date]).

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