Is HTT p.Pro3007Leu (c.9020C>T) pathogenic?

HTT p.Pro3007Leu (c.9020C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely pathogenic (0.6655); Very rare (popmax 0.000186%); Associated with Inborn genetic diseases.

What condition is associated with HTT p.Pro3007Leu (c.9020C>T)?

HTT p.Pro3007Leu (c.9020C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HTT p.Pro3007Leu (c.9020C>T) in the general population?

HTT p.Pro3007Leu (c.9020C>T) is very rare (popmax 0.000186%) (gnomAD).

What do computational predictors say about HTT p.Pro3007Leu (c.9020C>T)?

AlphaMissense predicts likely pathogenic (score 0.6655) — an in-silico prediction, not a clinical call.

HTT p.Pro3007Leu

c.9020C>T · rs2474096130 · VCV2274568

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000186%)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6655	likely pathogenic
REVEL	0.494	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000186%

Overall 0.000186% 3/1,612,482 alleles · very rare exomes 3/1,460,148 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,213
Finnishnot grpmax-eligible	0.00156%	64,006

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.Pro3007Leu
Coding: c.9020C>T
MANE Select: NM_001388492
dbSNP: rs2474096130
Type: single nucleotide variant
Location: chr4:3238575 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

Full HTT 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

HTT p.Arg416Cys Uncertain significance ★ ⚠ same condition
HTT p.Gln29Pro Uncertain significance ★ ⚠ same condition
HTT p.Gln31Pro Conflicting classifications of pathogenicity ★ ⚠ same condition
HTT p.Gln35Pro Uncertain significance ★ ⚠ same condition
HTT p.Pro41Gln Uncertain significance ★ ⚠ same condition
HTT p.Thr1720Ser Uncertain significance ★ ⚠ same condition
HTT p.Val1484Glu Uncertain significance ★ same condition
HTT c.889+6G>T 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/htt-p-pro3007leu (accessed [today's date]).

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