Is POLL p.Ser408= (c.1224T>C) pathogenic?

POLL p.Ser408= (c.1224T>C) is classified Benign in POLL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-04). Common (popmax 29.8%, nfe) — too common for a highly-penetrant pathogenic allele.

POLL p.Ser408=

Q: How common is POLL p.Ser408= (c.1224T>C) in the general population?

POLL p.Ser408= (c.1224T>C) is common (popmax 29.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1224T>C · rs3730476 · VCV1221687

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 29.8%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8	GERP -4.5
Overall
CADD	0.051	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 29.8% European (non-Finnish) · 351,027/1,179,620 alleles

Filtering AF 29.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 29.6%

Overall 27% 435,246/1,613,466 alleles · common exomes 398,644/1,461,350 · genomes 36,602/152,116 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	38.9%	3
European (non-Finnish)grpmax	29.8%	3
Ashkenazi Jewishnot grpmax-eligible	29%	3
Remaining individualsnot grpmax-eligible	25.7%	4
Finnishnot grpmax-eligible	24.9%	4
Middle Eastern	21.8%	5
African / African-American	18.3%	5
Admixed American	17.8%	6
South Asian	17%	6
East Asian	4.65%	21

Amish 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.Ser408=
Coding: c.1224T>C
MANE Select: NM_001174084
dbSNP: rs3730476
Type: single nucleotide variant
Location: chr10:101580387 (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 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.Arg438Trp 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-ser408 (accessed [today's date]).

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