Is DPYS p.Phe101Ile (c.301T>A) pathogenic?

DPYS p.Phe101Ile (c.301T>A) is classified Uncertain significance in DPYS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-24). AlphaMissense: likely pathogenic (0.9005); Ultra-rare (popmax 0.0283%, amr); Associated with Inborn genetic diseases.

What condition is associated with DPYS p.Phe101Ile (c.301T>A)?

DPYS p.Phe101Ile (c.301T>A) is associated with Inborn genetic diseases (ClinVar).

How common is DPYS p.Phe101Ile (c.301T>A) in the general population?

DPYS p.Phe101Ile (c.301T>A) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about DPYS p.Phe101Ile (c.301T>A)?

AlphaMissense predicts likely pathogenic (score 0.9005) — an in-silico prediction, not a clinical call.

DPYS p.Phe101Ile

c.301T>A · rs557472597 · VCV1468091

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9005 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9005	likely pathogenic
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -13.17	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 86 kb · p 0.4 · regional, not allelic
Overall
CADD	26.9	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 0.0283% Admixed American · 17/60,014 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00155% 25/1,614,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,530
Middle Eastern	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)	0.000339%	295,004

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: DPYS
Protein: p.Phe101Ile
Coding: c.301T>A
MANE Select: NM_001385
dbSNP: rs557472597
Type: single nucleotide variant
Location: chr8:104451368 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 1 PDB
Residue 101: a β-strand

Full DPYS 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

DPYS p.Phe101Ser Uncertain significance ★ ⚠ same residue
DPYS p.Ser379Arg Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Ala47Gly Uncertain significance ★★ ⚠ same condition
DPYS p.Ala491Val Uncertain significance ★★ ⚠ same condition
DPYS p.Asn347Ser Uncertain significance ★★ ⚠ same condition
DPYS p.Asp140Asn Uncertain significance ★★ ⚠ same condition
DPYS p.Asp309Tyr Uncertain significance ★★ ⚠ same condition
DPYS p.Glu115Lys Uncertain significance ★★ ⚠ 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/dpys-p-phe101ile (accessed [today's date]).

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