Is HTT p.Glu660Lys (c.1978G>A) pathogenic?

HTT p.Glu660Lys (c.1978G>A) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-25). AlphaMissense: likely benign (0.1351); Ultra-rare (popmax 0.0361%, eas); Associated with Lopes-Maciel-Rodan syndrome.

What condition is associated with HTT p.Glu660Lys (c.1978G>A)?

HTT p.Glu660Lys (c.1978G>A) is associated with Lopes-Maciel-Rodan syndrome (ClinVar).

How common is HTT p.Glu660Lys (c.1978G>A) in the general population?

HTT p.Glu660Lys (c.1978G>A) is ultra-rare (popmax 0.0361%, eas) (gnomAD).

What do computational predictors say about HTT p.Glu660Lys (c.1978G>A)?

AlphaMissense predicts likely benign (score 0.1351) — an in-silico prediction, not a clinical call.

HTT p.Glu660Lys

c.1978G>A · rs547978890 · VCV2582507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0361%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Lopes-Maciel-Rodan syndrome

Computational evidence

Protein change
AlphaMissense	0.1351	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 2, phastCons 1
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0361% East Asian · 16/44,298 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00114% 18/1,581,360 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0361%	2,769
Remaining individualsnot grpmax-eligible	0.00326%	30,629

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.Glu660Lys
Coding: c.1978G>A
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs547978890
Type: single nucleotide variant
Location: chr4:3130415 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Disease context

Lopes-Maciel-Rodan syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HTT p.Asp920Asn Uncertain significance ★★ same condition
HTT p.Gly2968Asp Uncertain significance ★★ same condition
HTT p.Leu1237Ile Uncertain significance ★★ ⚠ same condition
HTT p.Pro703Leu 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
HTT p.Leu2307= Likely pathogenic ★ 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-glu660lys (accessed [today's date]).

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