Is POLL p.Arg538Trp (c.1612C>T) pathogenic?

POLL p.Arg538Trp (c.1612C>T) is classified Uncertain significance in POLL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely benign (0.1981); Ultra-rare (popmax 0.0267%, afr).

How common is POLL p.Arg538Trp (c.1612C>T) in the general population?

POLL p.Arg538Trp (c.1612C>T) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about POLL p.Arg538Trp (c.1612C>T)?

AlphaMissense predicts likely benign (score 0.1981) — an in-silico prediction, not a clinical call.

POLL p.Arg538Trp

c.1612C>T · rs758883082 · VCV2324426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1981 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1981	likely benign
REVEL	0.453	indeterminate
SaProt	LLR -11.33	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 8.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,904 bp · p 0.00011 · 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 0.0267% African / African-American · 20/74,912 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00347% 56/1,613,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,746
Finnishnot grpmax-eligible	0.0047%	21,289
South Asian	0.00329%	30,361
European (non-Finnish)	0.00246%	40,691
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Arg538Trp
Coding: c.1612C>T
MANE Select: NM_001174084
dbSNP: rs758883082
Type: single nucleotide variant
Location: chr10:101579569 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.90 · 97 PDB

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

Similar variants

POLL p.Arg538Gln Uncertain significance ★ ⚠ same residue
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

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-arg538trp (accessed [today's date]).

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