Is HTT p.Gly697fs (c.2085del) pathogenic?

HTT p.Gly697fs (c.2085del) is classified Pathogenic in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). Very rare (popmax 0.000424%, nfe).

How common is HTT p.Gly697fs (c.2085del) in the general population?

HTT p.Gly697fs (c.2085del) is very rare (popmax 0.000424%, nfe) (gnomAD).

HTT p.Gly697fs

c.2085del · rs745583559 · VCV1464611

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP -0.068, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,062 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000411% 6/1,460,880 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)grpmax	0.000424%	235,812

Remaining individuals 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: HTT
Protein: p.Gly697fs
Coding: c.2085del
MANE Select: NM_001388492
dbSNP: rs745583559
Type: Deletion
Location: chr4:3131384 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Similar variants

HTT c.5369-9del Likely benign ★★ same type
HTT p.Gln33fs Likely pathogenic ★ same type
HTT p.Ser1941fs Pathogenic ★ same type
HTT c.2099-21_2099-13del Uncertain significance ★ same type
HTT c.747+4del Uncertain significance ★ same type
HTT c.7766-13_7766-8del Uncertain significance ★ same type
SLC6A4 c.*2091del Uncertain significance ★ same type
HTT c.264-17_264-14del Likely 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/htt-p-gly697fs (accessed [today's date]).

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