Is AASS p.Met166Lys (c.497T>A) pathogenic?

AASS p.Met166Lys (c.497T>A) is classified Uncertain significance in AASS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-29). AlphaMissense: likely pathogenic (0.8643); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AASS p.Met166Lys (c.497T>A)?

AASS p.Met166Lys (c.497T>A) is associated with Inborn genetic diseases (ClinVar).

How common is AASS p.Met166Lys (c.497T>A) in the general population?

AASS p.Met166Lys (c.497T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AASS p.Met166Lys (c.497T>A)?

AlphaMissense predicts likely pathogenic (score 0.8643) — an in-silico prediction, not a clinical call.

AASS p.Met166Lys

c.497T>A · rs2486071640 · VCV2227682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8643	likely pathogenic
REVEL	0.693	pathogenic-leaning
SaProt	LLR -13.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 0.0048 · regional, not allelic
Overall
CADD	23.9	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 8.47e-05% European (non-Finnish) · 1/1,179,948 alleles

Overall 6.84e-05% 1/1,461,656 alleles · very rare

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: AASS
Protein: p.Met166Lys
Coding: c.497T>A
MANE Select: NM_005763
dbSNP: rs2486071640
Type: single nucleotide variant
Location: chr7:122118606 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.73 · 9 PDB
Residue 166: the 'lysine-ketoglutarate reductase' region; an α-helix

Full AASS 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

AASS p.Asn34Lys Uncertain significance ★★ ⚠ same condition
AASS p.Asn865Ser Uncertain significance ★★ ⚠ same condition
AASS p.Gly167Cys Uncertain significance ★★ ⚠ same condition
AASS p.His846Arg Uncertain significance ★★ ⚠ same condition
AASS p.Ile491Met Uncertain significance ★★ ⚠ same condition
AASS p.Leu465Val Uncertain significance ★★ ⚠ same condition
AASS p.Ser474Leu Uncertain significance ★★ ⚠ same condition
AASS p.Ser664Pro 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/aass-p-met166lys (accessed [today's date]).

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