Is DDOST p.Phe429Val (c.1285T>G) pathogenic?

DDOST p.Phe429Val (c.1285T>G) is classified Uncertain significance in DDOST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.8776); Ultra-rare (popmax 0.0165%, mid).

How common is DDOST p.Phe429Val (c.1285T>G) in the general population?

DDOST p.Phe429Val (c.1285T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DDOST p.Phe429Val (c.1285T>G)?

AlphaMissense predicts likely pathogenic (score 0.8776) — an in-silico prediction, not a clinical call.

DDOST p.Phe429Val

c.1285T>G · VCV4238463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8776	likely pathogenic
REVEL	0.914	moderately pathogenic-leaning
SaProt	LLR -14.36	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 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,968 bp · p 0.046 · regional, not allelic
Overall
CADD	27.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F446V vs ClinVar F429V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000806% 13/1,613,890 alleles · ultra-rare exomes 13/1,461,582 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
African / African-American	0.00266%	37,524
East Asian	0.00223%	44,868
European (non-Finnish)	0.000763%	131,103

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: DDOST
Protein: p.Phe429Val
Coding: c.1285T>G
MANE Select: NM_005216
Type: single nucleotide variant
Location: chr1:20652414 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB

Full DDOST gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DDOST p.Phe429Leu Uncertain significance ★ ⚠ same residue
DDOST p.Phe429del Uncertain significance ★ same residue
DDOST p.Gln215His Pathogenic/Likely pathogenic ★★ same type
DDOST c.-18T>G Uncertain significance ★★ ⚠ same type
DDOST p.Ala11Val Uncertain significance ★★ ⚠ same type
DDOST p.Ala219Val Uncertain significance ★★ ⚠ same type
DDOST p.Ala232Ser Uncertain significance ★★ ⚠ same type
DDOST p.Ala415Thr 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/ddost-p-phe429val (accessed [today's date]).

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