Is HERC2 p.Pro2445Arg (c.7334C>G) pathogenic?

HERC2 p.Pro2445Arg (c.7334C>G) is classified Likely benign in HERC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1546); Rare (popmax 0.936%, afr); Associated with Inborn genetic diseases.

What condition is associated with HERC2 p.Pro2445Arg (c.7334C>G)?

HERC2 p.Pro2445Arg (c.7334C>G) is associated with Inborn genetic diseases (ClinVar).

How common is HERC2 p.Pro2445Arg (c.7334C>G) in the general population?

HERC2 p.Pro2445Arg (c.7334C>G) is rare (popmax 0.936%, afr) (gnomAD).

What do computational predictors say about HERC2 p.Pro2445Arg (c.7334C>G)?

AlphaMissense predicts likely benign (score 0.1546) — an in-silico prediction, not a clinical call.

HERC2 p.Pro2445Arg

c.7334C>G · VCV3284061

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1546 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.936%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1546	likely benign
REVEL	0.165	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 170 bp · p 4.9e-05 · regional, not allelic
Overall
CADD	17.73	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 0.936% African / African-American · 576/61,556 alleles

Filtering AF 0.872% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.847%

Overall 0.0492% 686/1,395,096 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.936%	107
Remaining individualsnot grpmax-eligible	0.081%	1,234
Middle Eastern	0.0571%	1,750
Admixed American	0.0473%	2,116
European (non-Finnish)	0.00348%	28,750
South Asian	0.00241%	41,411

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.Pro2445Arg
Coding: c.7334C>G
MANE Select: NM_004667
Type: single nucleotide variant
Location: chr15:28202493 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HERC2 p.Ala1253Thr Uncertain significance ★★ same condition
HERC2 p.Ala1454Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala200Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2331Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2458Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2671Gly Uncertain significance ★★ same condition
HERC2 p.Ala2948Ser Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala3095Ser Uncertain significance ★★ same condition

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-pro2445arg (accessed [today's date]).

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