Is POLL p.Asp459Gly (c.1376A>G) pathogenic?

POLL p.Asp459Gly (c.1376A>G) is classified Uncertain significance in POLL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.4266); Very rare (popmax 0.000678%, nfe).

How common is POLL p.Asp459Gly (c.1376A>G) in the general population?

POLL p.Asp459Gly (c.1376A>G) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about POLL p.Asp459Gly (c.1376A>G)?

AlphaMissense predicts ambiguous (score 0.4266) — an in-silico prediction, not a clinical call.

POLL p.Asp459Gly

c.1376A>G · VCV4141336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4266 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4266	ambiguous
REVEL	0.461	indeterminate
SaProt	LLR -14.69	damaging
Splicing
SpliceAI	Δ0.30	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,904 bp · p 0.00011 · regional, not allelic
Overall
CADD	33.0	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 0.000678% European (non-Finnish) · 8/1,179,488 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,612,770 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)grpmax	0.000678%	147,436

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: POLL
Protein: p.Asp459Gly
Coding: c.1376A>G
MANE Select: NM_001174084
Type: single nucleotide variant
Location: chr10:101579805 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.90 · 97 PDB
Residue 459: a β-strand

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

Similar variants

POLL c.1066-135C>A Benign ★★ same type
POLL c.1195-62A>G Benign ★★ same type
POLL c.1195-6T>C Benign ★★ same type
POLL c.573+42A>G Benign ★★ same type
POLL c.892-76T>C Benign ★★ same type
POLL c.892-95T>C Benign ★★ same type
POLL c.*68C>T Benign ★★ same type
POLL p.Arg438Trp Benign ★★ 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/poll-p-asp459gly (accessed [today's date]).

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