Is INTS8 p.Ser755Arg (c.2263A>C) pathogenic?

INTS8 p.Ser755Arg (c.2263A>C) is classified Benign/Likely benign in INTS8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-01). AlphaMissense: likely pathogenic (0.6636); Rare (popmax 0.691%, nfe).

How common is INTS8 p.Ser755Arg (c.2263A>C) in the general population?

INTS8 p.Ser755Arg (c.2263A>C) is rare (popmax 0.691%, nfe) (gnomAD).

What do computational predictors say about INTS8 p.Ser755Arg (c.2263A>C)?

AlphaMissense predicts likely pathogenic (score 0.6636) — an in-silico prediction, not a clinical call.

INTS8 p.Ser755Arg

c.2263A>C · rs150502842 · VCV782952

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6636 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.691%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6636	likely pathogenic
REVEL	0.123	moderately benign-leaning
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	24.0	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 0.691% European (non-Finnish) · 6,162/891,164 alleles

Filtering AF 0.677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.671%

Overall 0.523% 6,652/1,272,092 alleles · rare exomes 6,029/1,119,772 · genomes 623/152,320 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.75%	57
European (non-Finnish)grpmax	0.691%	145
Remaining individualsnot grpmax-eligible	0.414%	242
Admixed American	0.209%	477
African / African-American	0.128%	784
Finnishnot grpmax-eligible	0.0988%	1,013
Ashkenazi Jewishnot grpmax-eligible	0.0193%	5,186
South Asian	0.00793%	12,607

Amish 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.Ser755Arg
Coding: c.2263A>C
MANE Select: NM_017864
dbSNP: rs150502842
Type: single nucleotide variant
Location: chr8:94866159 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 755: 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.Arg359Ter Likely pathogenic ★ same type
INTS8 c.2762+1G>A 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/ints8-p-ser755arg (accessed [today's date]).

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