Is POLG p.Val437Phe (c.1309G>T) pathogenic?

POLG p.Val437Phe (c.1309G>T) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely pathogenic (0.9502); Very rare (popmax 0.000339%, nfe).

How common is POLG p.Val437Phe (c.1309G>T) in the general population?

POLG p.Val437Phe (c.1309G>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about POLG p.Val437Phe (c.1309G>T)?

AlphaMissense predicts likely pathogenic (score 0.9502) — an in-silico prediction, not a clinical call.

POLG p.Val437Phe

c.1309G>T · rs2509256288 · VCV2645691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9502	likely pathogenic
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	27.2	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 0.000339% European (non-Finnish) · 4/1,180,040 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,170 alleles · very rare exomes 4/1,461,838 · genomes 0/152,332 · 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: POLG
Protein: p.Val437Phe
Coding: c.1309G>T
MANE Select: NM_002693
dbSNP: rs2509256288
Type: single nucleotide variant
Location: chr15:89327291 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 437: a β-strand

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

Similar variants

POLG p.Val437= Conflicting classifications of pathogenicity ★ same residue
POLG c.3643+2T>C Pathogenic ★★★ same type
POLG p.Ala1105Pro Likely pathogenic ★★★ same type
POLG p.Arg1096Cys Likely pathogenic ★★★ same type
POLG p.Asp1184Asn Pathogenic ★★★ same type
POLG p.Gln1175Ter Likely pathogenic ★★★ same type
POLG p.Lys1191Asn Likely pathogenic ★★★ same type
POLG c.3483-14T>C 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/polg-p-val437phe (accessed [today's date]).

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