Is HERC2 p.Phe6fs (c.18_19del) pathogenic?

HERC2 p.Phe6fs (c.1819del) is classified Likely pathogenic in HERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-19). Ultra-rare (popmax 0.0164%, eas); Associated with HERC2-related disorders.

What condition is associated with HERC2 p.Phe6fs (c.18_19del)?

HERC2 p.Phe6fs (c.18_19del) is associated with HERC2-related disorders (ClinVar).

How common is HERC2 p.Phe6fs (c.18_19del) in the general population?

HERC2 p.Phe6fs (c.18_19del) is ultra-rare (popmax 0.0164%, eas) (gnomAD).

HERC2 p.Phe6fs

c.18_19del · VCV4923780

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, eas)

Conditions

HERC2-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 2 of 93
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% East Asian · 7/42,686 alleles

Filtering AF 0.00769% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00546%

Overall 0.00142% 14/984,824 alleles · ultra-rare exomes 13/834,888 · genomes 1/149,936 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0164%	6,098
South Asian	0.00667%	15,003
Remaining individualsnot grpmax-eligible	0.00473%	21,127

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.Phe6fs
Coding: c.18_19del
MANE Select: NM_004667
Type: Deletion
Location: chr15:28321415 (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 disorders

Similar variants

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
HERC2 c.801-7A>G Likely 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-phe6fs (accessed [today's date]).

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