Is HERC2 p.Arg577= (c.1731C>T) pathogenic?

HERC2 p.Arg577= (c.1731C>T) is classified Likely benign in HERC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-27). Ultra-rare (popmax 0.0786%, afr); Associated with HERC2-related disorder.

What condition is associated with HERC2 p.Arg577= (c.1731C>T)?

HERC2 p.Arg577= (c.1731C>T) is associated with HERC2-related disorder (ClinVar).

How common is HERC2 p.Arg577= (c.1731C>T) in the general population?

HERC2 p.Arg577= (c.1731C>T) is ultra-rare (popmax 0.0786%, afr) (gnomAD).

HERC2 p.Arg577=

c.1731C>T · rs138275638 · VCV3052736

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0786%, afr)

Conditions

HERC2-related disorder

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 -7.9
Overall
CADD	0.875	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0786% African / African-American · 59/75,038 alleles

Filtering AF 0.0625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0567%

Overall 0.00551% 89/1,614,142 alleles · ultra-rare exomes 43/1,461,872 · genomes 46/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0786%	1,272
Admixed American	0.0217%	4,617
Remaining individualsnot grpmax-eligible	0.0064%	15,626
East Asian	0.00446%	22,430
South Asian	0.00439%	22,771
European (non-Finnish)	0.000593%	168,576

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.Arg577=
Coding: c.1731C>T
MANE Select: NM_004667
dbSNP: rs138275638
Type: single nucleotide variant
Location: chr15:28265842 (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

HERC2-related disorder

Similar variants

HERC2 p.Arg577Pro Uncertain significance ★ ⚠ same residue
HERC2 p.Arg3560Trp Uncertain significance same condition
HERC2 p.Glu216Ter Uncertain significance same condition
HERC2 p.Gly2229Ala Uncertain significance ⚠ same condition
HERC2 c.11700+8A>C Likely benign same condition
HERC2 c.13414+3G>A Likely benign same condition
HERC2 c.3235+10T>A Benign same condition
HERC2 c.801-3C>G Benign 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-arg577 (accessed [today's date]).

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