Is INTU p.Arg157= (c.471A>G) pathogenic?

INTU p.Arg157= (c.471A>G) is classified Benign in INTU (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 69%, sas) — too common for a highly-penetrant pathogenic allele; Associated with orofaciodigital syndrome 17.

What condition is associated with INTU p.Arg157= (c.471A>G)?

INTU p.Arg157= (c.471A>G) is associated with orofaciodigital syndrome 17, short-rib thoracic dysplasia 20 with polydactyly (ClinVar).

INTU p.Arg157=

Q: How common is INTU p.Arg157= (c.471A>G) in the general population?

INTU p.Arg157= (c.471A>G) is common (popmax 69%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.471A>G · rs3749507 · VCV1249414

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 69%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

orofaciodigital syndrome 17

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -1.4, phastCons 0.048
Overall
CADD	6.706	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 69% South Asian · 62,819/91,064 alleles

Filtering AF 68.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 68.3%

Overall 53% 855,272/1,613,636 alleles · common exomes 770,349/1,461,768 · genomes 84,923/151,868 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	69%	1
Middle Eastern	66.6%	2
African / African-American	63.9%	2
Admixed American	58.8%	2
Ashkenazi Jewishnot grpmax-eligible	57.8%	2
Remaining individualsnot grpmax-eligible	55%	2
East Asian	53.6%	2
European (non-Finnish)	50.9%	2
Finnishnot grpmax-eligible	45.6%	2
Amishnot grpmax-eligible	39.2%	3

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.Arg157=
Coding: c.471A>G
MANE Select: NM_015693
dbSNP: rs3749507
Type: single nucleotide variant
Location: chr4:127643845 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.35 · 4 PDB

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

Disease context

orofaciodigital syndrome 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: short-rib thoracic dysplasia 20 with polydactyly

Similar variants

INTU p.Arg157Ter Conflicting classifications of pathogenicity ★ same residue
INTU p.Arg157Gln Uncertain significance ★ ⚠ same residue
INTU p.Arg843Cys Uncertain significance ★★ ⚠ same condition
INTU c.1450-9T>G Benign/Likely benign ★★ same condition
INTU c.683-16G>C Benign/Likely benign ★★ same condition
INTU p.Thr271= Benign ★★ same condition
INTU p.Glu355Ter Likely pathogenic ★ same condition
INTU p.Glu500Ala Likely pathogenic ★ ⚠ 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/intu-p-arg157 (accessed [today's date]).

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