Is ASAH1 p.Val72Met (c.214G>A) pathogenic?

ASAH1 p.Val72Met (c.214G>A) is classified Benign in ASAH1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0638); Common (popmax 60.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with spinal muscular atrophy-progressive myoclonic epilepsy syndrome.

What do computational predictors say about ASAH1 p.Val72Met (c.214G>A)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

ASAH1 p.Val72Met

Q: What condition is associated with ASAH1 p.Val72Met (c.214G>A)?

ASAH1 p.Val72Met (c.214G>A) is associated with spinal muscular atrophy-progressive myoclonic epilepsy syndrome, Farber lipogranulomatosis (ClinVar).

Q: How common is ASAH1 p.Val72Met (c.214G>A) in the general population?

ASAH1 p.Val72Met (c.214G>A) is common (popmax 60.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Spinal muscular atrophy-progressive myoclonic epilepsy syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.214G>A · rs1071645 · VCV259278

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 60.9%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.28	donor gain · deltas
Constraint at this position
Conservation	phyloP -1.1	GERP -3.8
Regional constraint	o/e 1.37	unconstrained · MANE · 27 kb · p 6.4e-16 · regional, not allelic
Overall
CADD	0.263	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 60.9% Admixed American · 35,639/58,476 alleles

Filtering AF 60.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 60.2%

Overall 47.8% 743,279/1,553,802 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	61%	2
Admixed Americangrpmax	60.9%	2
Amishnot grpmax-eligible	57.7%	2
South Asian	53.6%	2
European (non-Finnish)	48.4%	2
Middle Eastern	48.2%	2
Remaining individualsnot grpmax-eligible	47.6%	2
Finnishnot grpmax-eligible	41.3%	2
East Asian	39.9%	3
African / African-American	27.1%	4

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ASAH1
Protein: p.Val72Met
Coding: c.214G>A
MANE Select: NM_177924
dbSNP: rs1071645
Type: single nucleotide variant
Location: chr8:18071302 (GRCh38)
Gene constraint: LOEUF 1.435 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.97 · 2 PDB
Residue 72: a disulfide bond; a UniProt-annotated variant site (in); an α-helix

Full ASAH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinal muscular atrophy-progressive myoclonic epilepsy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Farber lipogranulomatosis

For Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ASAH1 c.1098+1G>T Pathogenic/Likely pathogenic ★★ same condition
ASAH1 c.125+1G>A Pathogenic ★★ same condition
ASAH1 c.457+4A>G Pathogenic/Likely pathogenic ★★ same condition
ASAH1 c.648+1G>C Likely pathogenic ★★ same condition
ASAH1 p.Arg254Gly Pathogenic ★★ same condition
ASAH1 p.Arg296Ter Pathogenic ★★ same condition
ASAH1 p.Arg333Cys Pathogenic/Likely pathogenic ★★ same condition
ASAH1 p.Arg333Gly 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/asah1-p-val72met (accessed [today's date]).

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