Is INTS2 p.Asn209Asp (c.625A>G) pathogenic?

INTS2 p.Asn209Asp (c.625A>G) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9941); Very rare (popmax 0.00164%, nfe).

How common is INTS2 p.Asn209Asp (c.625A>G) in the general population?

INTS2 p.Asn209Asp (c.625A>G) is very rare (popmax 0.00164%, nfe) (gnomAD).

What do computational predictors say about INTS2 p.Asn209Asp (c.625A>G)?

AlphaMissense predicts likely pathogenic (score 0.9941) — an in-silico prediction, not a clinical call.

INTS2 p.Asn209Asp

c.625A>G · VCV4275946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00164%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9941	likely pathogenic · top 7% in INTS2
REVEL	0.482	indeterminate
SaProt	LLR -10.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 N217D vs ClinVar N209D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00164% European (non-Finnish) · 19/1,159,612 alleles

Filtering AF 0.00105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000844%

Overall 0.00126% 20/1,585,136 alleles · very rare exomes 18/1,433,006 · genomes 2/152,130 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00164%	61,032
African / African-American	0.00134%	74,376

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.Asn209Asp
Coding: c.625A>G
MANE Select: NM_001351695
Type: single nucleotide variant
Location: chr17:61919424 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB
Residue 217 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-asn209asp (accessed [today's date]).

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