Is DAAM2 p.Pro548Leu (c.1643C>T) pathogenic?

DAAM2 p.Pro548Leu (c.1643C>T) is classified Uncertain significance in DAAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.1223); Very rare (popmax 0.00719%, eas); Associated with Inborn genetic diseases.

What condition is associated with DAAM2 p.Pro548Leu (c.1643C>T)?

DAAM2 p.Pro548Leu (c.1643C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DAAM2 p.Pro548Leu (c.1643C>T) in the general population?

DAAM2 p.Pro548Leu (c.1643C>T) is very rare (popmax 0.00719%, eas) (gnomAD).

What do computational predictors say about DAAM2 p.Pro548Leu (c.1643C>T)?

AlphaMissense predicts likely benign (score 0.1223) — an in-silico prediction, not a clinical call.

DAAM2 p.Pro548Leu

c.1643C>T · rs753628535 · VCV3079859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1223 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00719%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1223	likely benign
REVEL	0.281	benign-leaning
SaProt	LLR -9.37	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 5.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.46 · 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 0.00719% East Asian · 3/41,736 alleles

Filtering AF 0.00191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00103%

Overall 0.000263% 4/1,519,534 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00719%	13,912
European (non-Finnish)	8.94e-05%	1,118,886

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.Pro548Leu
Coding: c.1643C>T
MANE Select: NM_001201427
dbSNP: rs753628535
Type: single nucleotide variant
Location: chr6:39879275 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 80.02
Residue 548: a UniProt-annotated variant site (in nphs24; affects the regulation of filopodia formation); the fh1 domain; the 'disordered' region

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

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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-pro548leu (accessed [today's date]).

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