Is HERC2 p.Pro3337= (c.10011C>T) pathogenic?

HERC2 p.Pro3337= (c.10011C>T) is classified Likely benign in HERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). Common (popmax 6.46%, amr) — too common for a highly-penetrant pathogenic allele.

HERC2 p.Pro3337=

Q: How common is HERC2 p.Pro3337= (c.10011C>T) in the general population?

HERC2 p.Pro3337= (c.10011C>T) is common (popmax 6.46%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.10011C>T · VCV4923682

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 6.46%, amr) — 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.6
Overall
CADD	0.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.46% Admixed American · 3,205/49,606 alleles

Filtering AF 6.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.2%

Overall 2.65% 39,073/1,474,918 alleles · common exomes 34,883/1,333,504 · genomes 4,190/141,414 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	6.46%	15
Ashkenazi Jewishnot grpmax-eligible	5.96%	17
Middle Eastern	5.49%	18
South Asian	5.4%	19
Remaining individualsnot grpmax-eligible	3.1%	32
East Asian	2.99%	33
European (non-Finnish)	2.3%	43
Amishnot grpmax-eligible	2.19%	46
African / African-American	1.32%	75
Finnishnot grpmax-eligible	1.24%	80

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: HERC2
Protein: p.Pro3337=
Coding: c.10011C>T
MANE Select: NM_004667
Type: single nucleotide variant
Location: chr15:28174441 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)

Full HERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HERC2 c.4352-1G>A Likely pathogenic ★★ same type
HERC2 p.Arg1376Ter Pathogenic/Likely pathogenic ★★ same type
HERC2 c.12803-7C>A Uncertain significance ★★ same type
HERC2 c.8451+8C>A Uncertain significance ★★ same type
HERC2 p.Ala1253Thr Uncertain significance ★★ same type
HERC2 p.Ala1454Thr Uncertain significance ★★ ⚠ same type
HERC2 p.Ala200Val Uncertain significance ★★ ⚠ same type
HERC2 p.Ala2331Val Uncertain significance ★★ ⚠ 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/herc2-p-pro3337 (accessed [today's date]).

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