Is INTS6 p.Thr749Ala (c.2245A>G) pathogenic?

INTS6 p.Thr749Ala (c.2245A>G) is classified Benign in INTS6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-04). AlphaMissense: likely benign (0.055); Low-frequency (popmax 1.2%, afr).

How common is INTS6 p.Thr749Ala (c.2245A>G) in the general population?

INTS6 p.Thr749Ala (c.2245A>G) is low-frequency (popmax 1.2%, afr) (gnomAD).

What do computational predictors say about INTS6 p.Thr749Ala (c.2245A>G)?

AlphaMissense predicts likely benign (score 0.055) — an in-silico prediction, not a clinical call.

INTS6 p.Thr749Ala

c.2245A>G · rs149115928 · VCV787108

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.055 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.2%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.055	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.18	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 1.2	GERP 0.99, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 13 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	12.7	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 1.2% African / African-American · 903/75,022 alleles

Filtering AF 1.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.11%

Overall 0.0657% 1,060/1,613,914 alleles · low-frequency exomes 530/1,461,622 · genomes 530/152,292 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.2%	83
Admixed American	0.113%	882
Remaining individualsnot grpmax-eligible	0.11%	906
Middle Eastern	0.033%	3,030
European (non-Finnish)	0.00144%	69,404
South Asian	0.0011%	91,088

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.Thr749Ala
Coding: c.2245A>G
MANE Select: NM_012141
dbSNP: rs149115928
Type: single nucleotide variant
Location: chr13:51369170 (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.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
INTS6 p.Ala742Thr 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-thr749ala (accessed [today's date]).

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