Is ASAH1 p.Arg12Pro (c.35G>C) pathogenic?

ASAH1 p.Arg12Pro (c.35G>C) is classified Conflicting classifications of pathogenicity in ASAH1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-01). Rare (popmax 0.129%, nfe); Associated with ASAH1-related sphingolipidosis.

What condition is associated with ASAH1 p.Arg12Pro (c.35G>C)?

ASAH1 p.Arg12Pro (c.35G>C) is associated with ASAH1-related sphingolipidosis, self-limited epilepsy with centrotemporal spikes (ClinVar).

How common is ASAH1 p.Arg12Pro (c.35G>C) in the general population?

ASAH1 p.Arg12Pro (c.35G>C) is rare (popmax 0.129%, nfe) (gnomAD).

ASAH1 p.Arg12Pro

c.35G>C · rs147896487 · VCV433108

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.129%, nfe)

Conditions

ASAH1-related sphingolipidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.086	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -2.7
Overall
CADD	1.186	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.129% European (non-Finnish) · 1,523/1,179,828 alleles

Filtering AF 0.124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.121%

Overall 0.121% 1,945/1,613,634 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.48%	209
European (non-Finnish)grpmax	0.129%	775
Ashkenazi Jewishnot grpmax-eligible	0.0811%	1,233
Remaining individualsnot grpmax-eligible	0.0784%	1,275
South Asian	0.0198%	5,049
African / African-American	0.0187%	5,360
Admixed American	0.0167%	5,998

Finnish 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.Arg12Pro
Coding: c.35G>C
MANE Select: NM_177924 · reported on NM_004315
dbSNP: rs147896487
Type: single nucleotide variant
Location: chr8:18084767 (GRCh38)
Gene constraint: LOEUF 1.435 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.97 · 2 PDB

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

Disease context

Also linked: self-limited epilepsy with centrotemporal spikes

Similar variants

ASAH1 p.Leu12= Likely benign ★★ same residue
ASAH1 p.Pro362Thr Likely pathogenic ★★ same condition
ASAH1 p.Tyr207Phe Uncertain significance ★★ ⚠ same condition
ASAH1 p.Cys388Tyr Uncertain significance ★ ⚠ same condition
ASAH1 p.Leu12del Uncertain significance ★ same residue
ASAH1 p.Met210Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
ASAH1 c.1098+1G>T Pathogenic/Likely pathogenic ★★ same type
ASAH1 c.125+1G>A 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/asah1-p-arg12pro (accessed [today's date]).

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