Is AAGAB p.Met1Val (c.1A>G) pathogenic?

AAGAB p.Met1Val (c.1A>G) is classified Conflicting classifications of pathogenicity in AAGAB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-07-01). Very rare (popmax 0.00937%, afr).

How common is AAGAB p.Met1Val (c.1A>G) in the general population?

AAGAB p.Met1Val (c.1A>G) is very rare (popmax 0.00937%, afr) (gnomAD).

AAGAB p.Met1Val

c.1A>G · rs539301011 · VCV969403

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00937%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.345	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Overall
CADD	19.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00937% African / African-American · 7/74,716 alleles

Filtering AF 0.00505% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00465%

Overall 0.00545% 87/1,597,148 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00937%	10,674
European (non-Finnish)	0.00621%	16,090
Admixed American	0.00524%	19,073
Remaining individualsnot grpmax-eligible	0.00486%	20,589
South Asian	0.00112%	89,066

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.Met1Val
Coding: c.1A>G
MANE Select: NM_024666
dbSNP: rs539301011
Type: single nucleotide variant
Location: chr15:67254631 (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.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
AAGAB c.264+33A>G Benign ★★ same type
AAGAB c.536-95G>A Benign ★★ 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-met1val (accessed [today's date]).

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