Is POLH p.Phe707Val (c.2119T>G) pathogenic?

POLH p.Phe707Val (c.2119T>G) is classified Uncertain significance in POLH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-16). AlphaMissense: ambiguous (0.3633); Very rare (popmax 0.000509%, nfe); Associated with xeroderma pigmentosum.

What condition is associated with POLH p.Phe707Val (c.2119T>G)?

POLH p.Phe707Val (c.2119T>G) is associated with xeroderma pigmentosum (ClinVar).

How common is POLH p.Phe707Val (c.2119T>G) in the general population?

POLH p.Phe707Val (c.2119T>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

What do computational predictors say about POLH p.Phe707Val (c.2119T>G)?

AlphaMissense predicts ambiguous (score 0.3633) — an in-silico prediction, not a clinical call.

POLH p.Phe707Val

c.2119T>G · rs2127822760 · VCV1692930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.3633	ambiguous
REVEL	0.753	pathogenic-leaning
SaProt	LLR -12.36	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 0.00093 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,910 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,461,406 alleles · very rare

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.Phe707Val
Coding: c.2119T>G
MANE Select: NM_006502
dbSNP: rs2127822760
Type: single nucleotide variant
Location: chr6:43614534 (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

For Xeroderma pigmentosum (Orphanet):

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

Similar variants

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
POLH p.Gln632= Benign/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-phe707val (accessed [today's date]).

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