Is POLN p.Glu486Val (c.1457A>T) pathogenic?

POLN p.Glu486Val (c.1457A>T) is classified Uncertain significance in POLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.2157); Rare (popmax 0.248%, mid).

How common is POLN p.Glu486Val (c.1457A>T) in the general population?

POLN p.Glu486Val (c.1457A>T) is rare (popmax 0.248%, mid) (gnomAD).

What do computational predictors say about POLN p.Glu486Val (c.1457A>T)?

AlphaMissense predicts likely benign (score 0.2157) — an in-silico prediction, not a clinical call.

POLN p.Glu486Val

c.1457A>T · VCV4828707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2157 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.248%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2157	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -10.60	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 157 kb · p 0.54 · regional, not allelic
Overall
CADD	27.0	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 0.248% Middle Eastern · 15/6,050 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.0106% 171/1,610,252 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.248%	403
South Asian	0.0468%	2,138
Ashkenazi Jewishnot grpmax-eligible	0.0271%	3,690
Remaining individualsnot grpmax-eligible	0.016%	6,237
European (non-Finnish)	0.00781%	12,811
Admixed American	0.00506%	19,755
Finnishnot grpmax-eligible	0.00156%	64,004

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: POLN
Protein: p.Glu486Val
Coding: c.1457A>T
MANE Select: NM_181808
Type: single nucleotide variant
Location: chr4:2171099 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.70 · 4 PDB
Residue 486: an α-helix

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

Similar variants

POLN p.Phe711Leu Benign ★★ ⚠ same type
POLN p.Pro315Ser Benign ★★ same type
HAUS3 p.Ala76Thr Uncertain significance ★ ⚠ same type
HAUS3 p.Gln118Lys Uncertain significance ★ ⚠ same type
HAUS3 p.Gly518Glu Uncertain significance ★ ⚠ same type
HAUS3 p.His449Tyr Uncertain significance ★ ⚠ same type
HAUS3 p.Ile71Val Uncertain significance ★ ⚠ same type
HAUS3 p.Leu484Ile 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/poln-p-glu486val (accessed [today's date]).

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