Is POLN p.Ala695Pro (c.2083G>C) pathogenic?

POLN p.Ala695Pro (c.2083G>C) is classified Uncertain significance in POLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.3259); Very rare (popmax 0.00136%, nfe).

How common is POLN p.Ala695Pro (c.2083G>C) in the general population?

POLN p.Ala695Pro (c.2083G>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about POLN p.Ala695Pro (c.2083G>C)?

AlphaMissense predicts likely benign (score 0.3259) — an in-silico prediction, not a clinical call.

POLN p.Ala695Pro

c.2083G>C · VCV4141369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3259	likely benign
REVEL	0.657	pathogenic-leaning
SaProt	LLR -10.14	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.16	GERP -0.052, phastCons 0.005
Regional constraint	o/e 1.02	unconstrained · MANE · 157 kb · p 0.54 · regional, not allelic
Overall
CADD	20.9	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 0.00136% European (non-Finnish) · 16/1,180,040 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,613,664 alleles · very rare exomes 12/1,461,424 · genomes 4/152,240 · 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.Ala695Pro
Coding: c.2083G>C
MANE Select: NM_181808
Type: single nucleotide variant
Location: chr4:2085727 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.70 · 4 PDB
Residue 695: 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-ala695pro (accessed [today's date]).

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