Is INTS8 p.Thr677= (c.2031A>G) pathogenic?

INTS8 p.Thr677= (c.2031A>G) is classified Likely benign in INTS8 (ClinVar, No assertion criteria, 3 submitters; last evaluated 2019-12-09). Rare (popmax 0.246%, nfe); Associated with INTS8-related disorder.

What condition is associated with INTS8 p.Thr677= (c.2031A>G)?

INTS8 p.Thr677= (c.2031A>G) is associated with INTS8-related disorder (ClinVar).

How common is INTS8 p.Thr677= (c.2031A>G) in the general population?

INTS8 p.Thr677= (c.2031A>G) is rare (popmax 0.246%, nfe) (gnomAD).

INTS8 p.Thr677=

c.2031A>G · rs138818665 · VCV1285220

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.246%, nfe)

Conditions

INTS8-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.101	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.56	GERP -2.3, phastCons 0.74
Overall
CADD	4.155	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.246% European (non-Finnish) · 2,900/1,178,006 alleles

Filtering AF 0.239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.236%

Overall 0.211% 3,400/1,611,664 alleles · rare exomes 3,174/1,459,482 · genomes 226/152,182 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.08%	48
Finnishnot grpmax-eligible	0.358%	280
European (non-Finnish)grpmax	0.246%	406
Remaining individualsnot grpmax-eligible	0.228%	439
South Asian	0.0758%	1,319
Admixed American	0.0283%	3,530
African / African-American	0.028%	3,570
Middle Eastern	0.0167%	5,988
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
East Asian	0.00223%	44,800

Amish 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: INTS8
Protein: p.Thr677=
Coding: c.2031A>G
MANE Select: NM_017864
dbSNP: rs138818665
Type: single nucleotide variant
Location: chr8:94859587 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 677: an α-helix

Full INTS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

INTS8-related disorder

Similar variants

INTS8 c.2762+1G>A Uncertain significance ★ same condition
INTS8 c.131-9A>G Benign same condition
INTS8 c.2077-8T>C Benign same condition
INTS8 p.Glu100= Likely benign same condition
INTS8 p.Ile816Val Likely benign same condition
INTS8 p.Ile828Val Likely benign same condition
INTS8 p.Tyr499Cys Uncertain significance ★★ ⚠ same type
INTS8 c.1018-11G>A 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/ints8-p-thr677 (accessed [today's date]).

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