Is INTS2 p.Ser1054Cys (c.3161C>G) pathogenic?

INTS2 p.Ser1054Cys (c.3161C>G) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely pathogenic (0.5833); Very rare (popmax 0.00944%, nfe).

How common is INTS2 p.Ser1054Cys (c.3161C>G) in the general population?

INTS2 p.Ser1054Cys (c.3161C>G) is very rare (popmax 0.00944%, nfe) (gnomAD).

What do computational predictors say about INTS2 p.Ser1054Cys (c.3161C>G)?

AlphaMissense predicts likely pathogenic (score 0.5833) — an in-silico prediction, not a clinical call.

INTS2 p.Ser1054Cys

c.3161C>G · rs201686183 · VCV3110169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00944%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5833	likely pathogenic
REVEL	0.543	indeterminate
SaProt	LLR -7.82	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	27.4	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 S1062C vs ClinVar S1054C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00944% European (non-Finnish) · 111/1,176,418 alleles

Filtering AF 0.00794% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00746%

Overall 0.00708% 114/1,609,528 alleles · very rare exomes 106/1,457,362 · genomes 8/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00944%	10,598
African / African-American	0.00267%	37,425
Remaining individualsnot grpmax-eligible	0.0016%	62,316

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.Ser1054Cys
Coding: c.3161C>G
MANE Select: NM_001351695
dbSNP: rs201686183
Type: single nucleotide variant
Location: chr17:61869117 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB

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-ser1054cys (accessed [today's date]).

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