Is ASAH1 p.Pro126Ser (c.376C>T) pathogenic?

ASAH1 p.Pro126Ser (c.376C>T) is classified Uncertain significance in ASAH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-26). AlphaMissense: likely benign (0.1255); Very rare (popmax 0.00111%, sas).

How common is ASAH1 p.Pro126Ser (c.376C>T) in the general population?

ASAH1 p.Pro126Ser (c.376C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about ASAH1 p.Pro126Ser (c.376C>T)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

ASAH1 p.Pro126Ser

c.376C>T · rs199785411 · VCV1437092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -6.11	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 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.37	unconstrained · MANE · 27 kb · p 6.4e-16 · regional, not allelic
Overall
CADD	24.7	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 0.00111% South Asian · 1/89,780 alleles

Overall 6.91e-05% 1/1,448,080 alleles · very rare

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.Pro126Ser
Coding: c.376C>T
MANE Select: NM_177924
dbSNP: rs199785411
Type: single nucleotide variant
Location: chr8:18067226 (GRCh38)
Gene constraint: LOEUF 1.435 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.97 · 2 PDB
Residue 126: a disulfide bond

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

Similar variants

ASAH1 p.Pro126Thr Uncertain significance ★★ ⚠ same residue
ASAH1 p.Pro126Arg Uncertain significance ★ ⚠ same residue
ASAH1 p.Pro126fs Likely pathogenic ★ same residue
ASAH1 c.1098+1G>T Pathogenic/Likely pathogenic ★★ same type
ASAH1 c.125+1G>A Pathogenic ★★ same type
ASAH1 c.457+4A>G Pathogenic/Likely pathogenic ★★ same type
ASAH1 c.648+1G>C Likely pathogenic ★★ same type
ASAH1 c.786-2A>G 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/asah1-p-pro126ser (accessed [today's date]).

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