Is INTS11 p.Arg514Cys (c.1540C>T) pathogenic?

INTS11 p.Arg514Cys (c.1540C>T) is classified Uncertain significance in INTS11 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely benign (0.1891); Very rare (popmax 0.00588%, amr).

How common is INTS11 p.Arg514Cys (c.1540C>T) in the general population?

INTS11 p.Arg514Cys (c.1540C>T) is very rare (popmax 0.00588%, amr) (gnomAD).

What do computational predictors say about INTS11 p.Arg514Cys (c.1540C>T)?

AlphaMissense predicts likely benign (score 0.1891) — an in-silico prediction, not a clinical call.

INTS11 p.Arg514Cys

c.1540C>T · rs759883842 · VCV2562574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00588%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1891	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -9.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.087 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00588% Admixed American · 3/51,014 alleles

Filtering AF 0.0023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00204%

Overall 0.0031% 48/1,550,404 alleles · very rare exomes 40/1,398,546 · genomes 8/151,858 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00588%	17,005
African / African-American	0.00547%	18,296
Finnishnot grpmax-eligible	0.00342%	29,233
Remaining individualsnot grpmax-eligible	0.00333%	30,025
European (non-Finnish)	0.00314%	31,866
East Asian	0.00243%	41,232

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: INTS11
Protein: p.Arg514Cys
Coding: c.1540C>T
MANE Select: NM_017871
dbSNP: rs759883842
Type: single nucleotide variant
Location: chr1:1312293 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.82 · 15 PDB
Residue 514: a β-strand

Full INTS11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS11 p.Arg514= Likely benign ★ same residue
INTS11 c.28+1406C>T Uncertain significance ★★ same type
INTS11 p.Ala241Thr Uncertain significance ★★ ⚠ same type
INTS11 p.Arg231Cys Uncertain significance ★★ ⚠ same type
INTS11 p.Gln467His Uncertain significance ★★ ⚠ same type
INTS11 p.Glu227Lys Uncertain significance ★★ same type
INTS11 p.His157Arg Uncertain significance ★★ ⚠ same type
INTS11 c.1607+18C>A 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/ints11-p-arg514cys (accessed [today's date]).

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