Is POLH p.Ser497= (c.1491G>A) pathogenic?

POLH p.Ser497= (c.1491G>A) is classified Likely benign in POLH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-29). Ultra-rare (popmax 0.0735%, eas); Associated with xeroderma pigmentosum.

What condition is associated with POLH p.Ser497= (c.1491G>A)?

POLH p.Ser497= (c.1491G>A) is associated with xeroderma pigmentosum (ClinVar).

How common is POLH p.Ser497= (c.1491G>A) in the general population?

POLH p.Ser497= (c.1491G>A) is ultra-rare (popmax 0.0735%, eas) (gnomAD).

How is Xeroderma pigmentosum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

POLH p.Ser497=

c.1491G>A · rs145050695 · VCV1692923

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0735%, eas)

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.4
Overall
CADD	0.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0735% East Asian · 33/44,892 alleles

Filtering AF 0.0537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.047%

Overall 0.00297% 48/1,613,804 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0735%	1,360
African / African-American	0.00666%	15,007
South Asian	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0032%	31,250
European (non-Finnish)	0.000424%	236,007

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.Ser497=
Coding: c.1491G>A
MANE Select: NM_006502
dbSNP: rs145050695
Type: single nucleotide variant
Location: chr6:43613906 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 241 PDB
Residue 497: the 'disordered' region

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

Disease context

xeroderma pigmentosum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

POLH p.Ser497Leu Uncertain significance ★ ⚠ same residue
POLH p.Arg303Ter Pathogenic ★★ same condition
POLH p.Glu164Ter Pathogenic/Likely pathogenic ★★ same condition
POLH p.Lys70Asn Uncertain significance ★★ ⚠ same condition
POLH p.Ser138Leu Uncertain significance ★★ ⚠ same condition
POLH p.Thr156Met Uncertain significance ★★ ⚠ same condition
POLH p.Ala676= Benign/Likely benign ★★ same condition
POLH p.Gln524His Likely benign ★★ same condition

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-ser497 (accessed [today's date]).

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