Is AAGAB p.Ala2Thr (c.4G>A) pathogenic?

AAGAB p.Ala2Thr (c.4G>A) is classified Uncertain significance in AAGAB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-29). AlphaMissense: ambiguous (0.3769); Very rare (popmax 0.00264%, nfe).

How common is AAGAB p.Ala2Thr (c.4G>A) in the general population?

AAGAB p.Ala2Thr (c.4G>A) is very rare (popmax 0.00264%, nfe) (gnomAD).

What do computational predictors say about AAGAB p.Ala2Thr (c.4G>A)?

AlphaMissense predicts ambiguous (score 0.3769) — an in-silico prediction, not a clinical call.

AAGAB p.Ala2Thr

c.4G>A · rs369542537 · VCV1904118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00264%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3769	ambiguous
REVEL	0.202	benign-leaning
SaProt	LLR -7.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 52 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	25.3	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 0.00264% European (non-Finnish) · 31/1,175,494 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00165%

Overall 0.002% 32/1,599,406 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00264%	37,919
African / African-American	0.00134%	74,678

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: AAGAB
Protein: p.Ala2Thr
Coding: c.4G>A
MANE Select: NM_024666
dbSNP: rs369542537
Type: single nucleotide variant
Location: chr15:67254628 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 3 PDB

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

Similar variants

AAGAB p.Ala2Gly Uncertain significance ★ ⚠ same residue
AAGAB p.Ala2= Likely benign same residue
AAGAB p.Arg124Ter Pathogenic ★★ same type
AAGAB p.Arg161Ter Pathogenic ★★ same type
AAGAB p.Gln21Ter Pathogenic ★★ same type
AAGAB p.Ala74Pro Uncertain significance ★★ ⚠ same type
AAGAB p.Arg161Gln Uncertain significance ★★ ⚠ same type
AAGAB p.Leu92Val Uncertain significance ★★ ⚠ same type

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/aagab-p-ala2thr (accessed [today's date]).

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