Is INTS8 p.Tyr554Cys (c.1661A>G) pathogenic?

INTS8 p.Tyr554Cys (c.1661A>G) is classified Uncertain significance in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-23). AlphaMissense: likely pathogenic (0.6134); Very rare (popmax 0.00264%, nfe).

How common is INTS8 p.Tyr554Cys (c.1661A>G) in the general population?

INTS8 p.Tyr554Cys (c.1661A>G) is very rare (popmax 0.00264%, nfe) (gnomAD).

What do computational predictors say about INTS8 p.Tyr554Cys (c.1661A>G)?

AlphaMissense predicts likely pathogenic (score 0.6134) — an in-silico prediction, not a clinical call.

INTS8 p.Tyr554Cys

c.1661A>G · rs762284387 · VCV3110234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00264%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6134	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	27.5	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 0.00264% European (non-Finnish) · 31/1,172,552 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00165%

Overall 0.00224% 36/1,605,762 alleles · very rare exomes 32/1,453,596 · genomes 4/152,166 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00483%	20,725
Finnishnot grpmax-eligible	0.00312%	32,002
European (non-Finnish)grpmax	0.00264%	37,824

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr554Cys
Coding: c.1661A>G
MANE Select: NM_017864
dbSNP: rs762284387
Type: single nucleotide variant
Location: chr8:94853824 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 554: 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-tyr554cys (accessed [today's date]).

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