Is POLH p.Arg371Cys (c.1111C>T) pathogenic?

POLH p.Arg371Cys (c.1111C>T) is classified Conflicting classifications of pathogenicity in POLH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1654); Ultra-rare (popmax 0.08%, amr).

How common is POLH p.Arg371Cys (c.1111C>T) in the general population?

POLH p.Arg371Cys (c.1111C>T) is ultra-rare (popmax 0.08%, amr) (gnomAD).

What do computational predictors say about POLH p.Arg371Cys (c.1111C>T)?

AlphaMissense predicts likely benign (score 0.1654) — an in-silico prediction, not a clinical call.

POLH p.Arg371Cys

c.1111C>T · rs147564503 · VCV1305654

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1654 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1654	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -10.42	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 0.00093 · regional, not allelic
Overall
CADD	32.0	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 0.08% Admixed American · 48/59,982 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.0565% 912/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.08%	1,250
European (non-Finnish)	0.0695%	1,439
Remaining individualsnot grpmax-eligible	0.056%	1,785
African / African-American	0.00935%	10,700
Finnishnot grpmax-eligible	0.00312%	32,013

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.Arg371Cys
Coding: c.1111C>T
MANE Select: NM_006502
dbSNP: rs147564503
Type: single nucleotide variant
Location: chr6:43610590 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 241 PDB
Residue 371: a β-strand

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

Similar variants

POLH p.Arg371= Likely benign ★ 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-arg371cys (accessed [today's date]).

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