Is POLH p.Val36= (c.108T>C) pathogenic?

POLH p.Val36= (c.108T>C) is classified Likely benign in POLH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). Very rare (popmax 0.000339%, nfe).

How common is POLH p.Val36= (c.108T>C) in the general population?

POLH p.Val36= (c.108T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

POLH p.Val36=

c.108T>C · VCV4892128

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.63 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.2	GERP -3.7
Overall
CADD	4.461	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,842 alleles

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

Overall 0.000682% 11/1,613,848 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,147
European (non-Finnish)grpmax	0.000339%	294,961

Finnish 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: POLH
Protein: p.Val36=
Coding: c.108T>C
MANE Select: NM_006502
Type: single nucleotide variant
Location: chr6:43582427 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 241 PDB
Residue 36: the umuc domain; a β-strand

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

Similar variants

POLH p.Val36fs Pathogenic ★ same residue
POLH c.764+1G>A Pathogenic/Likely pathogenic ★★ same type
POLH p.Arg167Ter Pathogenic ★★ same type
POLH p.Arg303Ter Pathogenic ★★ same type
POLH p.Arg356Ter Pathogenic ★★ same type
POLH p.Glu164Ter Pathogenic/Likely pathogenic ★★ same type
POLH p.Ser213Ter Pathogenic/Likely pathogenic ★★ same type
POLH p.Thr191Pro Likely pathogenic ★★ 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/polh-p-val36 (accessed [today's date]).

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