Is INTS8 p.Met574Thr (c.1721T>C) pathogenic?

INTS8 p.Met574Thr (c.1721T>C) is classified Uncertain significance in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.5561); Very rare (popmax 0.0055%, sas).

How common is INTS8 p.Met574Thr (c.1721T>C) in the general population?

INTS8 p.Met574Thr (c.1721T>C) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about INTS8 p.Met574Thr (c.1721T>C)?

AlphaMissense predicts ambiguous (score 0.5561) — an in-silico prediction, not a clinical call.

INTS8 p.Met574Thr

c.1721T>C · VCV4276036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Computational evidence

Protein change
AlphaMissense	0.5561	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -2.53	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	22.8	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 0.0055% South Asian · 5/90,916 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000622% 10/1,607,204 alleles · very rare exomes 10/1,454,906 · genomes 0/152,298 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,183
Admixed American	0.00167%	60,006
European (non-Finnish)	0.000341%	293,438

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.Met574Thr
Coding: c.1721T>C
MANE Select: NM_017864
Type: single nucleotide variant
Location: chr8:94853884 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 574: an α-helix

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

Similar variants

INTS8 p.Met574Val 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-met574thr (accessed [today's date]).

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