Is INTS2 p.Leu1177Val (c.3529C>G) pathogenic?

INTS2 p.Leu1177Val (c.3529C>G) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: ambiguous (0.3674); Ultra-rare (popmax 0.0384%, amr).

How common is INTS2 p.Leu1177Val (c.3529C>G) in the general population?

INTS2 p.Leu1177Val (c.3529C>G) is ultra-rare (popmax 0.0384%, amr) (gnomAD).

What do computational predictors say about INTS2 p.Leu1177Val (c.3529C>G)?

AlphaMissense predicts ambiguous (score 0.3674) — an in-silico prediction, not a clinical call.

INTS2 p.Leu1177Val

c.3529C>G · VCV4275944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3674	ambiguous
REVEL	0.197	benign-leaning
SaProt	LLR -9.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Pangolin	Δ0.85	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	25.4	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 L1185V vs ClinVar L1177V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0384% Admixed American · 23/59,970 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00211% 34/1,611,036 alleles · ultra-rare exomes 28/1,458,806 · genomes 6/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0384%	2,607
Remaining individualsnot grpmax-eligible	0.00641%	15,597
European (non-Finnish)	0.000595%	168,202

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.Leu1177Val
Coding: c.3529C>G
MANE Select: NM_001351695
Type: single nucleotide variant
Location: chr17:61867619 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB
Residue 1185 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-leu1177val (accessed [today's date]).

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