Is ADSL p.Met76Val (c.226A>G) pathogenic?

ADSL p.Met76Val (c.226A>G) is classified Uncertain significance in ADSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely benign (0.0972); Absent from gnomAD v4.1.

How common is ADSL p.Met76Val (c.226A>G) in the general population?

ADSL p.Met76Val (c.226A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADSL p.Met76Val (c.226A>G)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

ADSL p.Met76Val

c.226A>G · VCV4527748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.402	indeterminate
SaProt	LLR -4.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Constraint at this position
Conservation	phyloP 3.3	GERP 0.097, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 20 kb · p 5.6e-07 · regional, not allelic
Overall
CADD	16.04	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADSL
Protein: p.Met76Val
Coding: c.226A>G
MANE Select: NM_000026
Type: single nucleotide variant
Location: chr22:40349904 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.82 · 4 PDB
Residue 76: an α-helix

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

Similar variants

ADSL p.Met76Leu Uncertain significance ★ ⚠ same residue
ADSL p.Met76Thr Uncertain significance ★ ⚠ same residue
ADSL c.1191+5G>C Pathogenic/Likely pathogenic ★★ same type
ADSL c.402+1G>T Likely pathogenic ★★ same type
ADSL c.482+1G>C Likely pathogenic ★★ same type
ADSL c.-49T>C Pathogenic/Likely pathogenic ★★ same type
ADSL p.Arg141Trp Pathogenic/Likely pathogenic ★★ same type
ADSL p.Arg149Ter Pathogenic/Likely pathogenic ★★ 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/adsl-p-met76val (accessed [today's date]).

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