Is INTU p.Arg741= (c.2223A>G) pathogenic?

INTU p.Arg741= (c.2223A>G) is classified Likely benign in INTU (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). Very rare (popmax 0.00533%, afr).

How common is INTU p.Arg741= (c.2223A>G) in the general population?

INTU p.Arg741= (c.2223A>G) is very rare (popmax 0.00533%, afr) (gnomAD).

INTU p.Arg741=

c.2223A>G · rs113308891 · VCV1916829

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.33	GERP -2.3, phastCons 0.036
Overall
CADD	7.802	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,050 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00112% 18/1,614,058 alleles · very rare exomes 14/1,461,748 · genomes 4/152,310 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,250
African / African-Americangrpmax	0.00533%	18,763
South Asian	0.00439%	22,769

Remaining individuals 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: INTU
Protein: p.Arg741=
Coding: c.2223A>G
MANE Select: NM_015693
dbSNP: rs113308891
Type: single nucleotide variant
Location: chr4:127706921 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.35 · 4 PDB
Residue 741: a UniProt-annotated variant site (in srtd7/20; in an srtd7/20 patient who also carries variant wdr35 l-311); a UniProt-annotated variant site (in srtd20; loss of subcellular location to cilium basal body, when tested in a heterologous system); the 'disordered' region

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

Similar variants

INTU p.Ala611Thr Uncertain significance ★★ ⚠ same type
INTU p.Ala804Val Uncertain significance ★★ ⚠ same type
INTU p.Arg119Thr Uncertain significance ★★ ⚠ same type
INTU p.Arg127Cys Uncertain significance ★★ ⚠ same type
INTU p.Arg510Gln Uncertain significance ★★ ⚠ same type
INTU p.Arg510Trp Uncertain significance ★★ ⚠ same type
INTU p.Arg665Cys Uncertain significance ★★ ⚠ same type
INTU p.Arg705Cys 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/intu-p-arg741 (accessed [today's date]).

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