Is DOP1A p.Pro153Arg (c.458C>G) pathogenic?

DOP1A p.Pro153Arg (c.458C>G) is classified Uncertain significance in DOP1A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely pathogenic (0.9799); Very rare (popmax 8.48e-05%, nfe).

How common is DOP1A p.Pro153Arg (c.458C>G) in the general population?

DOP1A p.Pro153Arg (c.458C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DOP1A p.Pro153Arg (c.458C>G)?

AlphaMissense predicts likely pathogenic (score 0.9799) — an in-silico prediction, not a clinical call.

DOP1A p.Pro153Arg

c.458C>G · rs2535207769 · VCV3085253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9799	likely pathogenic · top 10% in DOP1A
REVEL	0.55	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 23 kb · p 1.2e-08 · regional, not allelic
Overall
CADD	25.9	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 8.48e-05% European (non-Finnish) · 1/1,179,814 alleles

Overall 6.2e-05% 1/1,613,356 alleles · very rare exomes 1/1,461,124 · genomes 0/152,232 · 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: DOP1A
Protein: p.Pro153Arg
Coding: c.458C>G
MANE Select: NM_015018
dbSNP: rs2535207769
Type: single nucleotide variant
Location: chr6:83109047 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.63

Full DOP1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGM3 p.Arg492Ter Pathogenic/Likely pathogenic ★★ same type
PGM3 p.Ala531Val Uncertain significance ★★ ⚠ same type
PGM3 p.Arg505Gln Uncertain significance ★★ ⚠ same type
PGM3 p.Glu479Gln Uncertain significance ★★ ⚠ same type
PGM3 p.Ile534Thr Uncertain significance ★★ ⚠ same type
PGM3 p.Pro538Thr Uncertain significance ★★ ⚠ same type
PGM3 p.Val461Leu Uncertain significance ★★ ⚠ same type
PGM3 p.Val504Ile 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/dop1a-p-pro153arg (accessed [today's date]).

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