Is INTS6 p.Glu481Gly (c.1442A>G) pathogenic?

INTS6 p.Glu481Gly (c.1442A>G) is classified Uncertain significance in INTS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: ambiguous (0.4574); Ultra-rare (popmax 0.0187%, afr).

How common is INTS6 p.Glu481Gly (c.1442A>G) in the general population?

INTS6 p.Glu481Gly (c.1442A>G) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about INTS6 p.Glu481Gly (c.1442A>G)?

AlphaMissense predicts ambiguous (score 0.4574) — an in-silico prediction, not a clinical call.

INTS6 p.Glu481Gly

c.1442A>G · rs139832932 · VCV2327132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4574 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4574	ambiguous
REVEL	0.267	benign-leaning
SaProt	LLR -7.10	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 161 bp · p 0.23 · regional, not allelic
Overall
CADD	27.8	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 0.0187% African / African-American · 14/74,900 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.0013% 21/1,613,376 alleles · ultra-rare exomes 9/1,461,308 · genomes 12/152,068 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,350
Remaining individualsnot grpmax-eligible	0.00961%	10,410
East Asian	0.00223%	44,860

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: INTS6
Protein: p.Glu481Gly
Coding: c.1442A>G
MANE Select: NM_012141
dbSNP: rs139832932
Type: single nucleotide variant
Location: chr13:51378399 (GRCh38)
Gene constraint: LOEUF 0.23 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.80 · 9 PDB

Full INTS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS6 p.Thr749Ala Benign ★★ same type
INTS6 p.Arg206Cys Likely pathogenic ★ same type
INTS6 p.Arg610Ter Pathogenic ★ same type
INTS6 p.Gln185Ter Pathogenic ★ same type
INTS6 p.Gln228Glu Likely pathogenic ★ same type
INTS6 c.613+2T>C Uncertain significance ★ same type
INTS6 p.Ala44Gly Uncertain significance ★ ⚠ same type
INTS6 p.Ala530Ser 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/ints6-p-glu481gly (accessed [today's date]).

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