Is ASPH p.Glu506Val (c.1517A>T) pathogenic?

ASPH p.Glu506Val (c.1517A>T) is classified Uncertain significance in ASPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-03). AlphaMissense: ambiguous (0.3435); Rare (popmax 0.121%, afr); Associated with Inborn genetic diseases.

What condition is associated with ASPH p.Glu506Val (c.1517A>T)?

ASPH p.Glu506Val (c.1517A>T) is associated with Inborn genetic diseases (ClinVar).

How common is ASPH p.Glu506Val (c.1517A>T) in the general population?

ASPH p.Glu506Val (c.1517A>T) is rare (popmax 0.121%, afr) (gnomAD).

What do computational predictors say about ASPH p.Glu506Val (c.1517A>T)?

AlphaMissense predicts ambiguous (score 0.3435) — an in-silico prediction, not a clinical call.

ASPH p.Glu506Val

c.1517A>T · rs369603667 · VCV2198759

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3435 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.121%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3435	ambiguous
REVEL	0.35	indeterminate
SaProt	LLR -13.74	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.76, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	27.1	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 0.121% African / African-American · 91/74,934 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0937%

Overall 0.00713% 115/1,613,910 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.121%	823
Remaining individualsnot grpmax-eligible	0.0224%	4,463
Admixed American	0.01%	9,999
South Asian	0.0022%	45,530
European (non-Finnish)	0.00017%	589,971

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.Glu506Val
Coding: c.1517A>T
MANE Select: NM_004318
dbSNP: rs369603667
Type: single nucleotide variant
Location: chr8:61555943 (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 506: an α-helix

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.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
ASPH p.Ala505Asp 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/asph-p-glu506val (accessed [today's date]).

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