Is INTS8 p.Arg524Gly (c.1570A>G) pathogenic?

INTS8 p.Arg524Gly (c.1570A>G) is classified Uncertain significance in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-19). AlphaMissense: ambiguous (0.484); Rare (popmax 0.117%, afr).

How common is INTS8 p.Arg524Gly (c.1570A>G) in the general population?

INTS8 p.Arg524Gly (c.1570A>G) is rare (popmax 0.117%, afr) (gnomAD).

What do computational predictors say about INTS8 p.Arg524Gly (c.1570A>G)?

AlphaMissense predicts ambiguous (score 0.484) — an in-silico prediction, not a clinical call.

INTS8 p.Arg524Gly

c.1570A>G · rs151288845 · VCV2265047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.484 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.484	ambiguous
REVEL	0.211	benign-leaning
SaProt	LLR -8.64	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.4	GERP 0.23, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	21.4	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 0.117% African / African-American · 87/74,228 alleles

Filtering AF 0.0973% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0899%

Overall 0.00599% 96/1,602,910 alleles · rare exomes 48/1,450,572 · genomes 48/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.117%	853
Remaining individualsnot grpmax-eligible	0.00645%	15,507
Admixed American	0.00521%	19,182
European (non-Finnish)	0.00017%	587,769

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.Arg524Gly
Coding: c.1570A>G
MANE Select: NM_017864
dbSNP: rs151288845
Type: single nucleotide variant
Location: chr8:94851615 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 524: an α-helix

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

Similar variants

INTS8 p.Arg524Lys Uncertain significance ★ ⚠ same residue
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

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-arg524gly (accessed [today's date]).

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