Is DAB1 p.Leu154Phe (c.462G>C) pathogenic?

DAB1 p.Leu154Phe (c.462G>C) is classified Uncertain significance in DAB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely pathogenic (0.9863); Ultra-rare (popmax 0.0217%, amr).

How common is DAB1 p.Leu154Phe (c.462G>C) in the general population?

DAB1 p.Leu154Phe (c.462G>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about DAB1 p.Leu154Phe (c.462G>C)?

AlphaMissense predicts likely pathogenic (score 0.9863) — an in-silico prediction, not a clinical call.

DAB1 p.Leu154Phe

c.462G>C · VCV4009178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9863	likely pathogenic
REVEL	0.579	indeterminate
SaProt	LLR -11.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 119 kb · p 2.8e-08 · regional, not allelic
Overall
CADD	24.6	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 0.0217% Admixed American · 13/59,946 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000868% 14/1,613,472 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,611
European (non-Finnish)	8.48e-05%	1,179,870

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: DAB1
Protein: p.Leu154Phe
Coding: c.462G>C
MANE Select: NM_001365792
Type: single nucleotide variant
Location: chr1:57071618 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.20
Residue 154: the pid domain

Full DAB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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DAB1 p.Pro334Leu Uncertain significance ★★ ⚠ same type
DAB1 p.Pro376Ala Uncertain significance ★★ ⚠ same type
DAB1 p.Pro391Ser Uncertain significance ★★ ⚠ same type
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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/dab1-p-leu154phe (accessed [today's date]).

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