Is ASPH p.Ser69Phe (c.206C>T) pathogenic?

ASPH p.Ser69Phe (c.206C>T) is classified Uncertain significance in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-11). AlphaMissense: likely pathogenic (0.9605); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with ASPH p.Ser69Phe (c.206C>T)?

ASPH p.Ser69Phe (c.206C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ASPH p.Ser69Phe (c.206C>T) in the general population?

ASPH p.Ser69Phe (c.206C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ASPH p.Ser69Phe (c.206C>T)?

AlphaMissense predicts likely pathogenic (score 0.9605) — an in-silico prediction, not a clinical call.

ASPH p.Ser69Phe

c.206C>T · VCV3790088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9605	likely pathogenic
REVEL	0.653	pathogenic-leaning
SaProt	LLR -11.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	25.9	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 0.00223% East Asian · 1/44,870 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,490 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,870
European (non-Finnish)	0.00017%	589,897

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.Ser69Phe
Coding: c.206C>T
MANE Select: NM_004318
Type: single nucleotide variant
Location: chr8:61684086 (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.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-ser69phe (accessed [today's date]).

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