Is ASPH p.Phe337Leu (c.1011T>G) pathogenic?

ASPH p.Phe337Leu (c.1011T>G) is classified Uncertain significance in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely pathogenic (0.8237); Ultra-rare (popmax 0.037%, amr); Associated with Inborn genetic diseases.

What condition is associated with ASPH p.Phe337Leu (c.1011T>G)?

ASPH p.Phe337Leu (c.1011T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ASPH p.Phe337Leu (c.1011T>G) in the general population?

ASPH p.Phe337Leu (c.1011T>G) is ultra-rare (popmax 0.037%, amr) (gnomAD).

What do computational predictors say about ASPH p.Phe337Leu (c.1011T>G)?

AlphaMissense predicts likely pathogenic (score 0.8237) — an in-silico prediction, not a clinical call.

ASPH p.Phe337Leu

c.1011T>G · rs746450205 · VCV2398596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8237 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8237	likely pathogenic
REVEL	0.278	benign-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.57, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	21.0	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 0.037% Admixed American · 20/54,114 alleles

Filtering AF 0.0244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0204%

Overall 0.00133% 21/1,577,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.037%	2,706
Remaining individualsnot grpmax-eligible	0.00163%	61,210

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.Phe337Leu
Coding: c.1011T>G
MANE Select: NM_004318
dbSNP: rs746450205
Type: single nucleotide variant
Location: chr8:61583995 (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 337: 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.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-phe337leu (accessed [today's date]).

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