Is POLM p.Pro289Ser (c.865C>T) pathogenic?

POLM p.Pro289Ser (c.865C>T) is classified Uncertain significance in POLM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely benign (0.1216); Very rare (popmax 0.00267%, afr).

How common is POLM p.Pro289Ser (c.865C>T) in the general population?

POLM p.Pro289Ser (c.865C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about POLM p.Pro289Ser (c.865C>T)?

AlphaMissense predicts likely benign (score 0.1216) — an in-silico prediction, not a clinical call.

POLM p.Pro289Ser

c.865C>T · VCV3781665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1216	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.7	GERP 0.44, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,144 bp · p 0.89 · regional, not allelic
Overall
CADD	24.6	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 0.00267% African / African-American · 2/74,860 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000188% 3/1,596,050 alleles · very rare exomes 1/1,443,730 · genomes 2/152,320 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,430
East Asian	0.00226%	44,210

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: POLM
Protein: p.Pro289Ser
Coding: c.865C>T
MANE Select: NM_013284
Type: single nucleotide variant
Location: chr7:44074501 (GRCh38)
Gene constraint: LOEUF 1.177 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.39 · 129 PDB
Residue 289: an α-helix

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

Similar variants

POLM p.Ala183Val Uncertain significance ★ ⚠ same type
POLM p.Ala384Thr Uncertain significance ★ ⚠ same type
POLM p.Ala400Gly Uncertain significance ★ ⚠ same type
POLM p.Ala51Glu Uncertain significance ★ ⚠ same type
POLM p.Ala61Ser Uncertain significance ★ ⚠ same type
POLM p.Ala61Val Uncertain significance ★ ⚠ same type
POLM p.Arg122Cys Uncertain significance ★ ⚠ same type
POLM p.Arg122Gly 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/polm-p-pro289ser (accessed [today's date]).

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