Is POLM p.Arg446Ser (c.1336C>A) pathogenic?

POLM p.Arg446Ser (c.1336C>A) is classified Uncertain significance in POLM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: ambiguous (0.4151); Ultra-rare (popmax 0.0615%, sas).

How common is POLM p.Arg446Ser (c.1336C>A) in the general population?

POLM p.Arg446Ser (c.1336C>A) is ultra-rare (popmax 0.0615%, sas) (gnomAD).

What do computational predictors say about POLM p.Arg446Ser (c.1336C>A)?

AlphaMissense predicts ambiguous (score 0.4151) — an in-silico prediction, not a clinical call.

POLM p.Arg446Ser

c.1336C>A · VCV4570270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4151 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0615%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4151	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -7.73	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.9, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 9,144 bp · p 0.89 · regional, not allelic
Overall
CADD	21.7	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 0.0615% South Asian · 56/91,080 alleles

Filtering AF 0.0486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.044%

Overall 0.00384% 62/1,614,174 alleles · ultra-rare exomes 58/1,461,836 · genomes 4/152,338 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0615%	1,626
Remaining individualsnot grpmax-eligible	0.0064%	15,625
European (non-Finnish)	0.000169%	590,009

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.Arg446Ser
Coding: c.1336C>A
MANE Select: NM_013284
Type: single nucleotide variant
Location: chr7:44073687 (GRCh38)
Gene constraint: LOEUF 1.177 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.39 · 129 PDB
Residue 446: an α-helix

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

Similar variants

POLM p.Arg446Cys Uncertain significance ★ ⚠ same residue
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

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-arg446ser (accessed [today's date]).

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