Is ASPH p.Pro331Ala (c.991C>G) pathogenic?

ASPH p.Pro331Ala (c.991C>G) is classified Uncertain significance in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-21). AlphaMissense: likely benign (0.3191); Ultra-rare (popmax 0.017%, mid); Associated with Inborn genetic diseases.

What condition is associated with ASPH p.Pro331Ala (c.991C>G)?

ASPH p.Pro331Ala (c.991C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ASPH p.Pro331Ala (c.991C>G) in the general population?

ASPH p.Pro331Ala (c.991C>G) is ultra-rare (popmax 0.017%, mid) (gnomAD).

What do computational predictors say about ASPH p.Pro331Ala (c.991C>G)?

AlphaMissense predicts likely benign (score 0.3191) — an in-silico prediction, not a clinical call.

ASPH p.Pro331Ala

c.991C>G · VCV3436719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3191	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.99, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	23.9	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 0.017% Middle Eastern · 1/5,890 alleles

Filtering AF 0.00354% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00666% 103/1,547,568 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.153%	655
Middle Easterngrpmax	0.017%	5,890
Remaining individualsnot grpmax-eligible	0.005%	20,008
European (non-Finnish)	0.00456%	21,917
African / African-American	0.00279%	35,874
Admixed American	0.00196%	50,986
South Asian	0.0012%	83,344

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: ASPH
Protein: p.Pro331Ala
Coding: c.991C>G
MANE Select: NM_004318
Type: single nucleotide variant
Location: chr8:61584015 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 43 PDB

Full ASPH 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

ASPH p.Arg753His Uncertain significance ★★ ⚠ same condition
ASPH p.Glu506Val Uncertain significance ★★ same condition
ASPH p.Leu433Arg Uncertain significance ★★ ⚠ same condition
ASPH p.Ser299Asn Uncertain significance ★★ ⚠ same condition
ASPH p.Val214Met Uncertain significance ★★ ⚠ same condition
ASPH p.Val462Met Uncertain significance ★★ ⚠ same condition
ASPH p.Val83Ala Uncertain significance ★★ ⚠ same condition
ASPH p.Met188Thr Likely benign ★★ 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/asph-p-pro331ala (accessed [today's date]).

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