Is ADSL p.Met181Val (c.541A>G) pathogenic?

ADSL p.Met181Val (c.541A>G) is classified Uncertain significance in ADSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1118); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with ADSL p.Met181Val (c.541A>G)?

ADSL p.Met181Val (c.541A>G) is associated with Inborn genetic diseases, adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Met181Val (c.541A>G) in the general population?

ADSL p.Met181Val (c.541A>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ADSL p.Met181Val (c.541A>G)?

AlphaMissense predicts likely benign (score 0.1118) — an in-silico prediction, not a clinical call.

ADSL p.Met181Val

c.541A>G · rs768542145 · VCV577681

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1118 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1118	likely benign
REVEL	0.612	indeterminate
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 20 kb · p 5.6e-07 · regional, not allelic
Overall
CADD	21.0	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

Grpmax group 0.01% Admixed American · 6/59,990 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00124% 20/1,614,066 alleles · ultra-rare exomes 14/1,461,892 · genomes 6/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
African / African-American	0.00133%	74,928
South Asian	0.0011%	91,088
European (non-Finnish)	0.000847%	118,004

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: ADSL
Protein: p.Met181Val
Coding: c.541A>G
MANE Select: NM_000026
dbSNP: rs768542145
Type: single nucleotide variant
Location: chr22:40358922 (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 181: an α-helix

Full ADSL 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

Also linked: adenylosuccinate lyase deficiency

Similar variants

ADSL p.Met181Ile Uncertain significance ★ same residue
ADSL p.Met181Leu Uncertain significance ★ ⚠ same residue
ADSL c.1191+5G>C Pathogenic/Likely pathogenic ★★ same condition
ADSL c.402+1G>T Likely pathogenic ★★ same condition
ADSL c.482+1G>C Likely pathogenic ★★ same condition
ADSL c.-49T>C Pathogenic/Likely pathogenic ★★ same condition
ADSL p.Arg141Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ADSL p.Arg149Ter Pathogenic/Likely pathogenic ★★ 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/adsl-p-met181val (accessed [today's date]).

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