Is AAGAB p.Leu92Val (c.274C>G) pathogenic?

AAGAB p.Leu92Val (c.274C>G) is classified Uncertain significance in AAGAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.2653); Very rare (popmax 0.00873%, nfe).

How common is AAGAB p.Leu92Val (c.274C>G) in the general population?

AAGAB p.Leu92Val (c.274C>G) is very rare (popmax 0.00873%, nfe) (gnomAD).

What do computational predictors say about AAGAB p.Leu92Val (c.274C>G)?

AlphaMissense predicts likely benign (score 0.2653) — an in-silico prediction, not a clinical call.

AAGAB p.Leu92Val

c.274C>G · VCV3332030

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00873%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2653	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -11.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 52 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	24.7	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 0.00873% European (non-Finnish) · 103/1,179,962 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00651% 105/1,613,900 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00873%	11,456
Admixed American	0.00167%	59,986
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Leu92Val
Coding: c.274C>G
MANE Select: NM_024666
Type: single nucleotide variant
Location: chr15:67236495 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 3 PDB
Residue 92: a turn

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 c.264+33A>G Benign ★★ same type
AAGAB c.536-95G>A Benign ★★ same type
AAGAB c.618+18A>G 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-leu92val (accessed [today's date]).

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