Is DAAM2 p.Ala989Val (c.2966C>T) pathogenic?

DAAM2 p.Ala989Val (c.2966C>T) is classified Uncertain significance in DAAM2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-14). AlphaMissense: likely benign (0.1225); Ultra-rare (popmax 0.0518%, mid); Associated with Inborn genetic diseases.

What condition is associated with DAAM2 p.Ala989Val (c.2966C>T)?

DAAM2 p.Ala989Val (c.2966C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DAAM2 p.Ala989Val (c.2966C>T) in the general population?

DAAM2 p.Ala989Val (c.2966C>T) is ultra-rare (popmax 0.0518%, mid) (gnomAD).

What do computational predictors say about DAAM2 p.Ala989Val (c.2966C>T)?

AlphaMissense predicts likely benign (score 0.1225) — an in-silico prediction, not a clinical call.

DAAM2 p.Ala989Val

c.2966C>T · rs755311083 · VCV2401617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1225 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0518%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1225	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Pangolin	Δ0.21	gain · loss 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP 2.5, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.46 · regional, not allelic
Overall
CADD	24.1	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 0.0518% Middle Eastern · 3/5,788 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.0106% 170/1,607,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.413%	242
Middle Easterngrpmax	0.0518%	1,929
Remaining individualsnot grpmax-eligible	0.024%	4,158
African / African-American	0.0134%	7,489
Admixed American	0.005%	19,985
European (non-Finnish)	0.00136%	73,708
South Asian	0.0011%	90,854

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala989Val
Coding: c.2966C>T
MANE Select: NM_001201427
dbSNP: rs755311083
Type: single nucleotide variant
Location: chr6:39901456 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 80.02
Residue 989: 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

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.Glu956Lys Uncertain significance ★★ ⚠ same condition
DAAM2 p.Ile699Val Uncertain significance ★★ ⚠ same condition
DAAM2 p.Ala117Val Uncertain significance ★ ⚠ same condition
DAAM2 p.Ala167Thr 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-ala989val (accessed [today's date]).

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