Is POLH p.Ala433= (c.1299C>A) pathogenic?

POLH p.Ala433= (c.1299C>A) is classified Conflicting classifications of pathogenicity in POLH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0867%, afr); Associated with xeroderma pigmentosum.

What condition is associated with POLH p.Ala433= (c.1299C>A)?

POLH p.Ala433= (c.1299C>A) is associated with xeroderma pigmentosum, xeroderma pigmentosum variant type (ClinVar).

How common is POLH p.Ala433= (c.1299C>A) in the general population?

POLH p.Ala433= (c.1299C>A) is ultra-rare (popmax 0.0867%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

POLH p.Ala433=

c.1299C>A · rs140331414 · VCV910558

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, afr)

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 -0.88	GERP -2.7
Overall
CADD	7.323	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0867% African / African-American · 65/75,012 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.00533% 86/1,613,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0867%	1,154
Admixed American	0.0267%	3,747
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00017%	589,964

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.Ala433=
Coding: c.1299C>A
MANE Select: NM_006502
dbSNP: rs140331414
Type: single nucleotide variant
Location: chr6:43613714 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 241 PDB

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

Also linked: xeroderma pigmentosum variant type

For Xeroderma pigmentosum (Orphanet):

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

Similar variants

POLH c.764+1G>A Pathogenic/Likely pathogenic ★★ same condition
POLH p.Arg167Ter Pathogenic ★★ same condition
POLH p.Arg303Ter Pathogenic ★★ same condition
POLH p.Arg356Ter Pathogenic ★★ same condition
POLH p.Glu164Ter Pathogenic/Likely pathogenic ★★ same condition
POLH p.Ser213Ter Pathogenic/Likely pathogenic ★★ same condition
POLH p.Thr191Pro Likely pathogenic ★★ same condition
POLH c.272+4A>G Uncertain significance ★★ 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-ala433 (accessed [today's date]).

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