Is ASAH1 p.Ser34Pro (c.100T>C) pathogenic?

ASAH1 p.Ser34Pro (c.100T>C) is classified Uncertain significance in ASAH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-03). AlphaMissense: likely benign (0.3305); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with ASAH1 p.Ser34Pro (c.100T>C)?

ASAH1 p.Ser34Pro (c.100T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ASAH1 p.Ser34Pro (c.100T>C) in the general population?

ASAH1 p.Ser34Pro (c.100T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ASAH1 p.Ser34Pro (c.100T>C)?

AlphaMissense predicts likely benign (score 0.3305) — an in-silico prediction, not a clinical call.

ASAH1 p.Ser34Pro

c.100T>C · rs1800369463 · VCV1517948

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3305 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3305	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -3.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.37	unconstrained · MANE · 27 kb · p 6.4e-16 · regional, not allelic
Overall
CADD	25.4	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 0.0164% Middle Eastern · 1/6,084 alleles

Overall 0.000186% 3/1,614,038 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00133%	74,918
European (non-Finnish)	8.47e-05%	1,180,027

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.Ser34Pro
Coding: c.100T>C
MANE Select: NM_177924
dbSNP: rs1800369463
Type: single nucleotide variant
Location: chr8:18075566 (GRCh38)
Gene constraint: LOEUF 1.435 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.97 · 2 PDB
Residue 34: a disulfide bond

Full ASAH1 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

ASAH1 p.Phe34Ser Uncertain significance ★ same residue
ASAH1 p.Arg226Cys Uncertain significance ★★ ⚠ same condition
ASAH1 p.Arg343His Uncertain significance ★★ ⚠ same condition
ASAH1 p.Gln346Glu Uncertain significance ★★ ⚠ same condition
ASAH1 p.Glu258Val Uncertain significance ★★ ⚠ same condition
ASAH1 p.Glu352Lys Uncertain significance ★★ ⚠ same condition
ASAH1 p.Gly168Arg Uncertain significance ★★ ⚠ same condition
ASAH1 p.Gly284Glu 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/asah1-p-ser34pro (accessed [today's date]).

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