Is INTS2 p.His195Arg (c.584A>G) pathogenic?

INTS2 p.His195Arg (c.584A>G) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: ambiguous (0.4259); Ultra-rare (popmax 0.0165%, mid).

How common is INTS2 p.His195Arg (c.584A>G) in the general population?

INTS2 p.His195Arg (c.584A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about INTS2 p.His195Arg (c.584A>G)?

AlphaMissense predicts ambiguous (score 0.4259) — an in-silico prediction, not a clinical call.

INTS2 p.His195Arg

c.584A>G · rs373636658 · VCV2236228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4259 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4259	ambiguous
REVEL	0.142	moderately benign-leaning
SaProt	LLR -7.95	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 5	GERP 0.55, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	18.73	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM H203R vs ClinVar H195R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,070 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00301%

Overall 0.00206% 33/1,602,794 alleles · ultra-rare exomes 28/1,450,824 · genomes 5/151,970 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,070
Admixed American	0.0103%	9,740
Remaining individualsnot grpmax-eligible	0.00643%	15,541
African / African-American	0.00535%	18,681
European (non-Finnish)	0.00145%	69,078
South Asian	0.00113%	88,488

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: INTS2
Protein: p.His195Arg
Coding: c.584A>G
MANE Select: NM_001351695
dbSNP: rs373636658
Type: single nucleotide variant
Location: chr17:61919465 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB
Residue 203 UniProt numbering: an α-helix

Full INTS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS2 c.-17A>G Uncertain significance ★ ⚠ same type
INTS2 c.-1A>G Uncertain significance ★ ⚠ same type
INTS2 c.-3A>G Uncertain significance ★ ⚠ same type
INTS2 p.Ala1125Ser Uncertain significance ★ ⚠ same type
INTS2 p.Ala379Val Uncertain significance ★ same type
INTS2 p.Ala400Asp Uncertain significance ★ ⚠ same type
INTS2 p.Ala57Val Uncertain significance ★ ⚠ same type
INTS2 p.Ala599Val Uncertain significance ★ ⚠ 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/ints2-p-his195arg (accessed [today's date]).

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