Is ASPH p.Thr658Ala (c.1972A>G) pathogenic?

ASPH p.Thr658Ala (c.1972A>G) is classified Likely benign in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). AlphaMissense: likely benign (0.1181); Ultra-rare (popmax 0.0566%, nfe).

How common is ASPH p.Thr658Ala (c.1972A>G) in the general population?

ASPH p.Thr658Ala (c.1972A>G) is ultra-rare (popmax 0.0566%, nfe) (gnomAD).

What do computational predictors say about ASPH p.Thr658Ala (c.1972A>G)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

ASPH p.Thr658Ala

c.1972A>G · rs151278995 · VCV738239

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0566%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -11.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	24.8	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 0.0566% European (non-Finnish) · 668/1,179,756 alleles

Filtering AF 0.0531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0516%

Overall 0.0644% 1,040/1,613,860 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.493%	203
European (non-Finnish)grpmax	0.0566%	1,766
Remaining individualsnot grpmax-eligible	0.056%	1,785
Middle Eastern	0.0495%	2,019
Admixed American	0.0167%	6,003
African / African-American	0.008%	12,507
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
South Asian	0.0011%	91,082

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: ASPH
Protein: p.Thr658Ala
Coding: c.1972A>G
MANE Select: NM_004318
dbSNP: rs151278995
Type: single nucleotide variant
Location: chr8:61518052 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 43 PDB
Residue 658: an α-helix

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

Similar variants

ASPH p.Arg735Trp Likely pathogenic ★★ same type
ASPH p.Tyr565Ter Pathogenic/Likely pathogenic ★★ same type
ASPH p.Arg425Cys Uncertain significance ★★ ⚠ same type
ASPH p.Arg753His Uncertain significance ★★ ⚠ same type
ASPH p.Glu506Val Uncertain significance ★★ ⚠ same type
ASPH p.Leu433Arg Uncertain significance ★★ ⚠ same type
ASPH p.Ser299Asn Uncertain significance ★★ ⚠ same type
ASPH p.Val214Met Uncertain significance ★★ ⚠ 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/asph-p-thr658ala (accessed [today's date]).

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