Is ASPH p.Val66Ala (c.197T>C) pathogenic?

ASPH p.Val66Ala (c.197T>C) is classified Uncertain significance in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-05). AlphaMissense: likely pathogenic (0.7598); Very rare (popmax 0.00466%, nfe); Associated with facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome.

How common is ASPH p.Val66Ala (c.197T>C) in the general population?

ASPH p.Val66Ala (c.197T>C) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about ASPH p.Val66Ala (c.197T>C)?

AlphaMissense predicts likely pathogenic (score 0.7598) — an in-silico prediction, not a clinical call.

ASPH p.Val66Ala

Q: What condition is associated with ASPH p.Val66Ala (c.197T>C)?

ASPH p.Val66Ala (c.197T>C) is associated with facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (ClinVar).

c.197T>C · rs761398964 · VCV1333914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome

Computational evidence

Protein change
AlphaMissense	0.7598	likely pathogenic
REVEL	0.531	indeterminate
SaProt	LLR -12.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00466% European (non-Finnish) · 55/1,179,806 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00341% 55/1,613,828 alleles · very rare

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.Val66Ala
Coding: c.197T>C
MANE Select: NM_004318
dbSNP: rs761398964
Type: single nucleotide variant
Location: chr8:61684095 (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

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASPH p.Arg735Trp Likely pathogenic ★★ same condition
ASPH p.Tyr565Ter Pathogenic/Likely pathogenic ★★ same condition
ASPH c.1150-57G>A Benign ★★ same condition
ASPH c.1301-79C>G Benign ★★ same condition
ASPH c.1437+27G>A Benign ★★ same condition
ASPH c.1626+10A>G Benign ★★ same condition
ASPH c.1900+6T>C Benign ★★ same condition
ASPH c.2127-6C>T 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-val66ala (accessed [today's date]).

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