Is ASPH p.Val727Ile (c.2179G>A) pathogenic?

ASPH p.Val727Ile (c.2179G>A) is classified Uncertain significance in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: ambiguous (0.5024); Ultra-rare (popmax 0.0392%, nfe).

How common is ASPH p.Val727Ile (c.2179G>A) in the general population?

ASPH p.Val727Ile (c.2179G>A) is ultra-rare (popmax 0.0392%, nfe) (gnomAD).

What do computational predictors say about ASPH p.Val727Ile (c.2179G>A)?

AlphaMissense predicts ambiguous (score 0.5024) — an in-silico prediction, not a clinical call.

ASPH p.Val727Ile

c.2179G>A · rs147092046 · VCV2168369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5024 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0392%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5024	ambiguous
REVEL	0.271	benign-leaning
SaProt	LLR -10.91	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	25.1	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 0.0392% European (non-Finnish) · 462/1,179,606 alleles

Filtering AF 0.0362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.035%

Overall 0.0301% 486/1,613,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0392%	2,553
Remaining individualsnot grpmax-eligible	0.024%	4,163
Admixed American	0.01%	9,983
African / African-American	0.00267%	37,505
Finnishnot grpmax-eligible	0.00156%	64,006

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.Val727Ile
Coding: c.2179G>A
MANE Select: NM_004318
dbSNP: rs147092046
Type: single nucleotide variant
Location: chr8:61503457 (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 727: a β-strand

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-val727ile (accessed [today's date]).

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