Is DDOST p.Leu34Pro (c.101T>C) pathogenic?

DDOST p.Leu34Pro (c.101T>C) is classified Uncertain significance in DDOST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-18). AlphaMissense: likely pathogenic (0.984); Very rare (popmax 0.0011%, sas).

How common is DDOST p.Leu34Pro (c.101T>C) in the general population?

DDOST p.Leu34Pro (c.101T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DDOST p.Leu34Pro (c.101T>C)?

AlphaMissense predicts likely pathogenic (score 0.984) — an in-silico prediction, not a clinical call.

DDOST p.Leu34Pro

c.101T>C · rs1249881543 · VCV2476260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.984	likely pathogenic
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -13.78	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 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,968 bp · p 0.046 · regional, not allelic
Overall
CADD	32.0	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 L51P vs ClinVar L34P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,096 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,954 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,096
European (non-Finnish)	0.000678%	147,505

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.Leu34Pro
Coding: c.101T>C
MANE Select: NM_005216
dbSNP: rs1249881543
Type: single nucleotide variant
Location: chr1:20661250 (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.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
DDOST p.Arg237His Uncertain significance ★★ ⚠ same type
DDOST p.Arg280Cys 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-leu34pro (accessed [today's date]).

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