Is POLH p.Ser83Phe (c.248C>T) pathogenic?

POLH p.Ser83Phe (c.248C>T) is classified Uncertain significance in POLH (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1306); Ultra-rare (popmax 0.0201%, eas); Associated with xeroderma pigmentosum variant type.

What condition is associated with POLH p.Ser83Phe (c.248C>T)?

POLH p.Ser83Phe (c.248C>T) is associated with xeroderma pigmentosum variant type (ClinVar).

How common is POLH p.Ser83Phe (c.248C>T) in the general population?

POLH p.Ser83Phe (c.248C>T) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

How is Xeroderma pigmentosum variant inherited?

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

What do computational predictors say about POLH p.Ser83Phe (c.248C>T)?

AlphaMissense predicts likely benign (score 0.1306) — an in-silico prediction, not a clinical call.

POLH p.Ser83Phe

c.248C>T · rs774770256 · VCV911728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1306 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum variant type

Computational evidence

Protein change
AlphaMissense	0.1306	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.73 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.087	GERP -3.5
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 0.00093 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0201% East Asian · 9/44,868 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00062% 10/1,613,884 alleles · ultra-rare exomes 5/1,461,770 · genomes 5/152,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,985
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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.Ser83Phe
Coding: c.248C>T
MANE Select: NM_006502
dbSNP: rs774770256
Type: single nucleotide variant
Location: chr6:43583117 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 241 PDB
Residue 83: the umuc domain; a β-strand

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

Disease context

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

For Xeroderma pigmentosum variant (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult

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-ser83phe (accessed [today's date]).

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