Is DOP1B p.Pro153His (c.458C>A) pathogenic?

DOP1B p.Pro153His (c.458C>A) is classified Uncertain significance in DOP1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.7222); Very rare (popmax 0.000678%, nfe).

How common is DOP1B p.Pro153His (c.458C>A) in the general population?

DOP1B p.Pro153His (c.458C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about DOP1B p.Pro153His (c.458C>A)?

AlphaMissense predicts likely pathogenic (score 0.7222) — an in-silico prediction, not a clinical call.

DOP1B p.Pro153His

c.458C>A · VCV4244272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7222 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7222	likely pathogenic
REVEL	0.568	indeterminate
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 129 kb · p 0.0008 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,616 alleles

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

Overall 0.000496% 8/1,611,854 alleles · very rare exomes 8/1,459,788 · genomes 0/152,066 · joint denominator

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: DOP1B
Protein: p.Pro153His
Coding: c.458C>A
MANE Select: NM_001320714
Type: single nucleotide variant
Location: chr21:36200468 (GRCh38)
Gene constraint: LOEUF 0.831 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.36

Full DOP1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOP1B p.Ile343Met Uncertain significance ★★ ⚠ same type
DOP1B p.Pro1079Ser Uncertain significance ★★ ⚠ same type
DOP1B p.Val124Leu Uncertain significance ★★ ⚠ same type
DOP1B p.Ala2159= Benign ★★ same type
DOP1B p.Ala649Val Benign ★★ same type
DOP1B p.Ala969= Benign ★★ same type
DOP1B p.Arg1938His Benign ★★ same type
DOP1B p.Asn726= Benign/Likely benign ★★ 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/dop1b-p-pro153his (accessed [today's date]).

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