Is INTS8 p.Asn411His (c.1231A>C) pathogenic?

INTS8 p.Asn411His (c.1231A>C) is classified Uncertain significance in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely benign (0.1112); Ultra-rare (popmax 0.0338%, amr).

How common is INTS8 p.Asn411His (c.1231A>C) in the general population?

INTS8 p.Asn411His (c.1231A>C) is ultra-rare (popmax 0.0338%, amr) (gnomAD).

What do computational predictors say about INTS8 p.Asn411His (c.1231A>C)?

AlphaMissense predicts likely benign (score 0.1112) — an in-silico prediction, not a clinical call.

INTS8 p.Asn411His

c.1231A>C · rs200147343 · VCV2535904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1112	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -10.54	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	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 0.0338% Admixed American · 20/59,168 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.00162% 26/1,603,420 alleles · ultra-rare exomes 10/1,451,062 · genomes 16/152,358 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0338%	2,958
Remaining individualsnot grpmax-eligible	0.00644%	15,529
African / African-American	0.00268%	37,375

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.Asn411His
Coding: c.1231A>C
MANE Select: NM_017864
dbSNP: rs200147343
Type: single nucleotide variant
Location: chr8:94842459 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB

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

Similar variants

INTS8 p.Asn411Asp 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-asn411his (accessed [today's date]).

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