Is POLM p.Arg446Cys (c.1336C>T) pathogenic?

POLM p.Arg446Cys (c.1336C>T) is classified Uncertain significance in POLM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely benign (0.1212); Ultra-rare (popmax 0.0164%, mid).

How common is POLM p.Arg446Cys (c.1336C>T) in the general population?

POLM p.Arg446Cys (c.1336C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about POLM p.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.1212) — an in-silico prediction, not a clinical call.

POLM p.Arg446Cys

c.1336C>T · rs550516150 · VCV2565447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1212	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.0031% 50/1,614,056 alleles · ultra-rare exomes 44/1,461,836 · genomes 6/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
African / African-American	0.00934%	10,705
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,008
European (non-Finnish)	0.00288%	34,707
Finnishnot grpmax-eligible	0.00156%	64,020

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.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_013284
dbSNP: rs550516150
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.Arg446Ser 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-arg446cys (accessed [today's date]).

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