Is INTS6 p.Ser856= (c.2568A>G) pathogenic?

INTS6 p.Ser856= (c.2568A>G) is classified Benign in INTS6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-11). Common (popmax 6.56%, eas) — too common for a highly-penetrant pathogenic allele; Associated with INTS6-related disorder.

What condition is associated with INTS6 p.Ser856= (c.2568A>G)?

INTS6 p.Ser856= (c.2568A>G) is associated with INTS6-related disorder (ClinVar).

INTS6 p.Ser856=

Q: How common is INTS6 p.Ser856= (c.2568A>G) in the general population?

INTS6 p.Ser856= (c.2568A>G) is common (popmax 6.56%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2568A>G · rs61749884 · VCV3037731

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 6.56%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

INTS6-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.6	GERP 2.2, phastCons 1
Overall
CADD	14.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.56% East Asian · 2,873/43,798 alleles

Filtering AF 6.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.28%

Overall 1.23% 18,958/1,539,298 alleles · common exomes 17,230/1,387,050 · genomes 1,728/152,248 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	6.56%	15
South Asian	3.84%	26
Ashkenazi Jewishnot grpmax-eligible	3.7%	27
Middle Eastern	2.66%	38
Remaining individualsnot grpmax-eligible	1.83%	55
Admixed American	1.33%	75
European (non-Finnish)	0.823%	122
Finnishnot grpmax-eligible	0.494%	202
Amishnot grpmax-eligible	0.329%	304
African / African-American	0.239%	418

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.Ser856=
Coding: c.2568A>G
MANE Select: NM_012141
dbSNP: rs61749884
Type: single nucleotide variant
Location: chr13:51367807 (GRCh38)
Gene constraint: LOEUF 0.23 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.80 · 9 PDB
Residue 856: an α-helix

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

Disease context

INTS6-related disorder

Similar variants

INTS6 p.Gln228Glu Likely pathogenic ★ same condition
INTS6 p.Val381Gly Uncertain significance ★ ⚠ same condition
INTS6 c.1275+1G>A Uncertain significance same condition
INTS6 p.Arg550Ter Uncertain significance same condition
INTS6 p.Gly30= Uncertain significance same condition
INTS6 c.340-3T>C Benign same condition
INTS6 p.Ala738Gly Likely benign same condition
INTS6 p.Asp518= Likely benign same condition

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-ser856 (accessed [today's date]).

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