Is HTT p.Pro703Leu (c.2108C>T) pathogenic?

HTT p.Pro703Leu (c.2108C>T) is classified Uncertain significance in HTT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-22). AlphaMissense: likely benign (0.3045); Ultra-rare (popmax 0.0504%, mid); Associated with Huntington disease.

What condition is associated with HTT p.Pro703Leu (c.2108C>T)?

HTT p.Pro703Leu (c.2108C>T) is associated with Huntington disease, Lopes-Maciel-Rodan syndrome (ClinVar).

How common is HTT p.Pro703Leu (c.2108C>T) in the general population?

HTT p.Pro703Leu (c.2108C>T) is ultra-rare (popmax 0.0504%, mid) (gnomAD).

How is Huntington disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HTT p.Pro703Leu (c.2108C>T)?

AlphaMissense predicts likely benign (score 0.3045) — an in-silico prediction, not a clinical call.

HTT p.Pro703Leu

c.2108C>T · rs768047421 · VCV417742

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3045 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0504%, mid)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Huntington disease

Computational evidence

Protein change
AlphaMissense	0.3045	likely benign
REVEL	0.657	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.1, phastCons 0.79
Overall
CADD	25.7	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 0.0504% Middle Eastern · 3/5,956 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00428% 69/1,612,578 alleles · ultra-rare exomes 63/1,460,470 · genomes 6/152,108 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.088%	1,136
Middle Easterngrpmax	0.0504%	1,985
South Asian	0.0154%	6,499
Remaining individualsnot grpmax-eligible	0.00801%	12,483
African / African-American	0.00401%	24,939
East Asian	0.00223%	44,852
Admixed American	0.00167%	59,704
European (non-Finnish)	0.00136%	73,712

Ashkenazi Jewish 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.Pro703Leu
Coding: c.2108C>T
MANE Select: NM_001388492
dbSNP: rs768047421
Type: single nucleotide variant
Location: chr4:3131647 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Disease context

Huntington disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lopes-Maciel-Rodan syndrome

For Huntington disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-9 / 100 000 (Greece)

Similar variants

HTT p.Asp920Asn Uncertain significance ★★ same condition
HTT p.Gly2084Arg Uncertain significance ★★ same condition
HTT p.Gly2968Asp Uncertain significance ★★ same condition
HTT p.Leu1237Ile Uncertain significance ★★ ⚠ same condition
HTT p.Val2500Ile Uncertain significance ★★ ⚠ same condition
HTT c.7765+10G>A Benign/Likely benign ★★ same condition
HTT p.Thr1260Met Benign ★★ same condition
HTT p.Val1546= Benign/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/htt-p-pro703leu (accessed [today's date]).

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