Is INTS8 p.Arg539Cys (c.1615C>T) pathogenic?

INTS8 p.Arg539Cys (c.1615C>T) is classified Uncertain significance in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely benign (0.3375); Very rare (popmax 0.00788%, sas).

How common is INTS8 p.Arg539Cys (c.1615C>T) in the general population?

INTS8 p.Arg539Cys (c.1615C>T) is very rare (popmax 0.00788%, sas) (gnomAD).

What do computational predictors say about INTS8 p.Arg539Cys (c.1615C>T)?

AlphaMissense predicts likely benign (score 0.3375) — an in-silico prediction, not a clinical call.

INTS8 p.Arg539Cys

c.1615C>T · rs768433116 · VCV2555155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00788%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3375	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -10.30	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	28.2	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 0.00788% South Asian · 7/88,850 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.000937% 15/1,601,332 alleles · very rare exomes 13/1,449,280 · genomes 2/152,052 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00788%	12,693
East Asian	0.00458%	21,850
Admixed American	0.00352%	28,446
African / African-American	0.00135%	73,850
European (non-Finnish)	0.000255%	391,939

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.Arg539Cys
Coding: c.1615C>T
MANE Select: NM_017864
dbSNP: rs768433116
Type: single nucleotide variant
Location: chr8:94851660 (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.Arg539His 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-arg539cys (accessed [today's date]).

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