Is INTS8 p.Pro72Leu (c.215C>T) pathogenic?

INTS8 p.Pro72Leu (c.215C>T) is classified Uncertain significance in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.6298); Very rare (popmax 0.000764%, nfe).

How common is INTS8 p.Pro72Leu (c.215C>T) in the general population?

INTS8 p.Pro72Leu (c.215C>T) is very rare (popmax 0.000764%, nfe) (gnomAD).

What do computational predictors say about INTS8 p.Pro72Leu (c.215C>T)?

AlphaMissense predicts likely pathogenic (score 0.6298) — an in-silico prediction, not a clinical call.

INTS8 p.Pro72Leu

c.215C>T · VCV4276049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6298 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000764%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6298	likely pathogenic
REVEL	0.388	indeterminate
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	27.1	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 0.000764% European (non-Finnish) · 9/1,178,558 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,612,150 alleles · very rare exomes 8/1,460,202 · genomes 1/151,948 · joint denominator

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.Pro72Leu
Coding: c.215C>T
MANE Select: NM_017864
Type: single nucleotide variant
Location: chr8:94824977 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 72: an α-helix

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-pro72leu (accessed [today's date]).

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