Is DAAM2 p.Arg990Cys (c.2968C>T) pathogenic?

DAAM2 p.Arg990Cys (c.2968C>T) is classified Uncertain significance in DAAM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.3213); Ultra-rare (popmax 0.0173%, mid); Associated with Inborn genetic diseases.

What condition is associated with DAAM2 p.Arg990Cys (c.2968C>T)?

DAAM2 p.Arg990Cys (c.2968C>T) is associated with Inborn genetic diseases, nephrotic syndrome, type 24 (ClinVar).

How common is DAAM2 p.Arg990Cys (c.2968C>T) in the general population?

DAAM2 p.Arg990Cys (c.2968C>T) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about DAAM2 p.Arg990Cys (c.2968C>T)?

AlphaMissense predicts likely benign (score 0.3213) — an in-silico prediction, not a clinical call.

DAAM2 p.Arg990Cys

c.2968C>T · VCV4237286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3213	likely benign
REVEL	0.491	indeterminate
SaProt	LLR -11.15	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.46 · regional, not allelic
Overall
CADD	26.8	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 0.0173% Middle Eastern · 1/5,766 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0137% 221/1,607,322 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,766
European (non-Finnish)	0.0168%	5,956
Remaining individualsnot grpmax-eligible	0.016%	6,237
African / African-American	0.012%	8,318
Finnishnot grpmax-eligible	0.00169%	59,036
Admixed American	0.00167%	59,940
South Asian	0.0011%	90,828

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.Arg990Cys
Coding: c.2968C>T
MANE Select: NM_001201427
Type: single nucleotide variant
Location: chr6:39901458 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 80.02
Residue 990: a UniProt-annotated variant site (in nphs24; affects the regulation of filopodia formation); the fh2 domain

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.Arg990His Uncertain significance ★ ⚠ same residue
DAAM2 p.Arg990Leu Likely benign ⚠ same residue
DAAM2 p.Arg335Trp Uncertain significance ★★ ⚠ same condition
DAAM2 p.Arg676Trp 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

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-arg990cys (accessed [today's date]).

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