Is INTS2 p.Ser348Asn (c.1043G>A) pathogenic?

INTS2 p.Ser348Asn (c.1043G>A) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: likely benign (0.111); Ultra-rare (popmax 0.0495%, mid).

How common is INTS2 p.Ser348Asn (c.1043G>A) in the general population?

INTS2 p.Ser348Asn (c.1043G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about INTS2 p.Ser348Asn (c.1043G>A)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

INTS2 p.Ser348Asn

c.1043G>A · rs372765802 · VCV2382873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S356N vs ClinVar S348N) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,056 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00765% 122/1,594,344 alleles · ultra-rare exomes 106/1,442,162 · genomes 16/152,182 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
Remaining individualsnot grpmax-eligible	0.0339%	2,946
African / African-American	0.0308%	3,247
South Asian	0.0149%	6,716
Admixed American	0.0106%	9,477
European (non-Finnish)	0.00479%	20,895

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.Ser348Asn
Coding: c.1043G>A
MANE Select: NM_001351695
dbSNP: rs372765802
Type: single nucleotide variant
Location: chr17:61907546 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB
Residue 356 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-ser348asn (accessed [today's date]).

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