Is ASPH p.Val214Met (c.640G>A) pathogenic?

ASPH p.Val214Met (c.640G>A) is classified Uncertain significance in ASPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-06). AlphaMissense: likely benign (0.0733); Very rare (popmax 0.00352%, amr); Associated with Inborn genetic diseases.

What condition is associated with ASPH p.Val214Met (c.640G>A)?

ASPH p.Val214Met (c.640G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ASPH p.Val214Met (c.640G>A) in the general population?

ASPH p.Val214Met (c.640G>A) is very rare (popmax 0.00352%, amr) (gnomAD).

What do computational predictors say about ASPH p.Val214Met (c.640G>A)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

ASPH p.Val214Met

c.640G>A · rs752226869 · VCV1917486

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.79	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 -0.68	GERP -2
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	8.805	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 0.00352% Admixed American · 2/56,824 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00117%

Overall 0.00202% 32/1,584,260 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00352%	28,412
Remaining individualsnot grpmax-eligible	0.00327%	30,558
African / African-American	0.00272%	36,805
East Asian	0.00229%	43,610
European (non-Finnish)	0.00206%	48,585
South Asian	0.00119%	84,296

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.Val214Met
Coding: c.640G>A
MANE Select: NM_004318
dbSNP: rs752226869
Type: single nucleotide variant
Location: chr8:61644612 (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.Val214= Likely benign same residue
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.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-val214met (accessed [today's date]).

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