Is POLN p.Ile558Ser (c.1673T>G) pathogenic?

POLN p.Ile558Ser (c.1673T>G) is classified Uncertain significance in POLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.8245); Very rare (popmax 0.00134%, afr).

How common is POLN p.Ile558Ser (c.1673T>G) in the general population?

POLN p.Ile558Ser (c.1673T>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about POLN p.Ile558Ser (c.1673T>G)?

AlphaMissense predicts likely pathogenic (score 0.8245) — an in-silico prediction, not a clinical call.

POLN p.Ile558Ser

c.1673T>G · VCV4141386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8245 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8245	likely pathogenic · top 6% in POLN
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -14.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.32	acceptor loss, 20 bp away · masked 0 · deltas
Pangolin	Δ0.20	gain · loss 0.00 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 157 kb · p 0.54 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00134% African / African-American · 1/74,870 alleles

Overall 6.21e-05% 1/1,611,234 alleles · very rare exomes 0/1,459,006 · genomes 1/152,228 · 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: POLN
Protein: p.Ile558Ser
Coding: c.1673T>G
MANE Select: NM_181808
Type: single nucleotide variant
Location: chr4:2156846 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.70 · 4 PDB

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-ile558ser (accessed [today's date]).

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