Is POLL p.Arg438Trp (c.1312C>T) pathogenic?

POLL p.Arg438Trp (c.1312C>T) is classified Benign in POLL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-04). AlphaMissense: likely benign (0.0828); Common (popmax 21.9%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about POLL p.Arg438Trp (c.1312C>T)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

POLL p.Arg438Trp

Q: How common is POLL p.Arg438Trp (c.1312C>T) in the general population?

POLL p.Arg438Trp (c.1312C>T) is common (popmax 21.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1312C>T · rs3730477 · VCV1248188

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 21.9%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -1.6, phastCons 0.91
Regional constraint	o/e 0.86	unconstrained · MANE · 7,904 bp · p 0.00011 · regional, not allelic
Overall
CADD	25.0	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 21.9% European (non-Finnish) · 258,538/1,179,342 alleles

Filtering AF 21.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.8%

Overall 19.6% 316,880/1,613,192 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	24%	4
Amishnot grpmax-eligible	22.4%	4
European (non-Finnish)grpmax	21.9%	5
Remaining individualsnot grpmax-eligible	19%	5
Finnishnot grpmax-eligible	18.7%	5
Middle Eastern	18.2%	5
South Asian	12.8%	8
Admixed American	12.5%	8
African / African-American	6.6%	15
East Asian	4.55%	22

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: POLL
Protein: p.Arg438Trp
Coding: c.1312C>T
MANE Select: NM_001174084
dbSNP: rs3730477
Type: single nucleotide variant
Location: chr10:101580299 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.90 · 97 PDB
Residue 438: a UniProt-annotated variant site (changed dna polymerase activity characterized by decreased fidelity and unchanged polymerization capacity; changed function in dna double-strand break repair by non-homologous end joining and homologous recombination; no effect on 5'-deoxyribose-5-phosphate lyase activity); a β-strand

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

Similar variants

POLL c.1066-135C>A Benign ★★ same type
POLL c.1195-62A>G Benign ★★ same type
POLL c.1195-6T>C Benign ★★ same type
POLL c.573+42A>G Benign ★★ same type
POLL c.892-76T>C Benign ★★ same type
POLL c.892-95T>C Benign ★★ same type
POLL c.*68C>T Benign ★★ same type
POLL p.Ser408= Benign ★★ 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/poll-p-arg438trp (accessed [today's date]).

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