Is INTS8 p.Lys547Glu (c.1639A>G) pathogenic?

INTS8 p.Lys547Glu (c.1639A>G) is classified Uncertain significance in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-13). AlphaMissense: likely pathogenic (0.7732); Ultra-rare (popmax 0.0252%, nfe).

How common is INTS8 p.Lys547Glu (c.1639A>G) in the general population?

INTS8 p.Lys547Glu (c.1639A>G) is ultra-rare (popmax 0.0252%, nfe) (gnomAD).

What do computational predictors say about INTS8 p.Lys547Glu (c.1639A>G)?

AlphaMissense predicts likely pathogenic (score 0.7732) — an in-silico prediction, not a clinical call.

INTS8 p.Lys547Glu

c.1639A>G · VCV3860868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7732	likely pathogenic
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -5.14	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	27.3	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 0.0252% European (non-Finnish) · 295/1,171,938 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.0197% 312/1,586,494 alleles · ultra-rare exomes 303/1,434,288 · genomes 9/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0252%	3,973
Remaining individualsnot grpmax-eligible	0.0244%	4,099
African / African-American	0.00274%	36,467

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.Lys547Glu
Coding: c.1639A>G
MANE Select: NM_017864
Type: single nucleotide variant
Location: chr8:94851684 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB

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

Similar variants

INTS8 p.Tyr499Cys Uncertain significance ★★ ⚠ same type
INTS8 c.1018-11G>A Benign ★★ same type
INTS8 p.Ala898= Benign ★★ same type
INTS8 p.Gly437Glu Likely benign ★★ same type
INTS8 p.His922= Benign ★★ same type
INTS8 p.Ser710= Benign ★★ same type
INTS8 p.Ser755Arg Benign/Likely benign ★★ ⚠ same type
INTS8 p.Arg359Ter Likely pathogenic ★ 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-lys547glu (accessed [today's date]).

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