Is POLN p.Ser655Phe (c.1964C>T) pathogenic?

POLN p.Ser655Phe (c.1964C>T) is classified Uncertain significance in POLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1535); Very rare (popmax 0.00223%, eas).

How common is POLN p.Ser655Phe (c.1964C>T) in the general population?

POLN p.Ser655Phe (c.1964C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about POLN p.Ser655Phe (c.1964C>T)?

AlphaMissense predicts likely benign (score 0.1535) — an in-silico prediction, not a clinical call.

POLN p.Ser655Phe

c.1964C>T · rs1209335735 · VCV2272685

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1535	likely benign
REVEL	0.629	indeterminate
SaProt	LLR -11.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.25	donor loss, 18 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 8.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 157 kb · p 0.54 · regional, not allelic
Overall
CADD	26.7	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 0.00223% East Asian · 1/44,832 alleles

Overall 6.24e-05% 1/1,602,716 alleles · very rare exomes 1/1,450,362 · genomes 0/152,354 · 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.Ser655Phe
Coding: c.1964C>T
MANE Select: NM_181808
dbSNP: rs1209335735
Type: single nucleotide variant
Location: chr4:2128131 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.70 · 4 PDB
Residue 655: 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-ser655phe (accessed [today's date]).

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