Is POLN p.Ser625Pro (c.1873T>C) pathogenic?

POLN p.Ser625Pro (c.1873T>C) is classified Uncertain significance in POLN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: ambiguous (0.5475); Ultra-rare (popmax 0.0335%, eas).

How common is POLN p.Ser625Pro (c.1873T>C) in the general population?

POLN p.Ser625Pro (c.1873T>C) is ultra-rare (popmax 0.0335%, eas) (gnomAD).

What do computational predictors say about POLN p.Ser625Pro (c.1873T>C)?

AlphaMissense predicts ambiguous (score 0.5475) — an in-silico prediction, not a clinical call.

POLN p.Ser625Pro

c.1873T>C · VCV3422318

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5475 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0335%, eas)

Computational evidence

Protein change
AlphaMissense	0.5475	ambiguous
REVEL	0.303	indeterminate
SaProt	LLR -9.70	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 157 kb · p 0.54 · regional, not allelic
Overall
CADD	24.2	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 0.0335% East Asian · 15/44,806 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.00113% 18/1,597,874 alleles · ultra-rare exomes 13/1,445,660 · genomes 5/152,214 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0335%	2,987
Remaining individualsnot grpmax-eligible	0.00484%	20,654

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.Ser625Pro
Coding: c.1873T>C
MANE Select: NM_181808
Type: single nucleotide variant
Location: chr4:2128222 (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-ser625pro (accessed [today's date]).

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