Is HTT p.Leu701Arg (c.2102T>G) pathogenic?

HTT p.Leu701Arg (c.2102T>G) is classified Uncertain significance in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-09). AlphaMissense: likely benign (0.2701); Ultra-rare (popmax 0.0374%, nfe).

How common is HTT p.Leu701Arg (c.2102T>G) in the general population?

HTT p.Leu701Arg (c.2102T>G) is ultra-rare (popmax 0.0374%, nfe) (gnomAD).

What do computational predictors say about HTT p.Leu701Arg (c.2102T>G)?

AlphaMissense predicts likely benign (score 0.2701) — an in-silico prediction, not a clinical call.

HTT p.Leu701Arg

c.2102T>G · rs200178417 · VCV1393738

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0374%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.2701	likely benign
REVEL	0.81	moderately pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.95 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Overall
CADD	26.4	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 0.0374% European (non-Finnish) · 441/1,179,146 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0334%

Overall 0.033% 532/1,612,376 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.108%	928
European (non-Finnish)grpmax	0.0374%	2,674
Remaining individualsnot grpmax-eligible	0.024%	4,160
African / African-American	0.00534%	18,716
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,528
East Asian	0.00223%	44,848
Admixed American	0.00167%	59,716

Finnish 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.Leu701Arg
Coding: c.2102T>G
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs200178417
Type: single nucleotide variant
Location: chr4:3131641 (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.889+6G>T Uncertain significance ★★ same type
HTT p.Ala2739Thr Uncertain significance ★★ same type
HTT p.Arg1654Trp Uncertain significance ★★ same type
HTT p.Arg1945Trp Uncertain significance ★★ same type
HTT p.Asp1157Gly Uncertain significance ★★ same type
HTT p.Asp920Asn Uncertain significance ★★ same type
HTT p.Glu449Ala Uncertain significance ★★ ⚠ same type
HTT p.Gly2084Arg 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-leu701arg (accessed [today's date]).

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