Is GDNF p.Arg74= (c.222A>G) pathogenic?

GDNF p.Arg74= (c.222A>G) is classified Likely benign in GDNF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-01-12). Ultra-rare (popmax 0.0427%, afr); Associated with Hirschsprung disease, susceptibility to, 3.

What condition is associated with GDNF p.Arg74= (c.222A>G)?

GDNF p.Arg74= (c.222A>G) is associated with Hirschsprung disease, susceptibility to, 3 (ClinVar).

How common is GDNF p.Arg74= (c.222A>G) in the general population?

GDNF p.Arg74= (c.222A>G) is ultra-rare (popmax 0.0427%, afr) (gnomAD).

GDNF p.Arg74=

c.222A>G · rs139694199 · VCV227376

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, afr)

Conditions

Hirschsprung disease, susceptibility to, 3

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 1.3	GERP -0.35, phastCons 1
Overall
CADD	8.089	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0427% African / African-American · 32/75,018 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00223% 36/1,613,632 alleles · ultra-rare exomes 14/1,461,298 · genomes 22/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0427%	2,344
Admixed American	0.00667%	14,996

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: GDNF
Protein: p.Arg74=
Coding: c.222A>G
MANE Select: NM_000514
dbSNP: rs139694199
Type: single nucleotide variant
Location: chr5:37816065 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 75.29 · 4 PDB

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

Disease context

Hirschsprung disease, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GDNF c.*2213G>A Uncertain significance ★★ same condition
GDNF c.*2828T>A Uncertain significance ★★ same condition
GDNF p.Arg116Gln Uncertain significance ★★ ⚠ same condition
GDNF c.-51A>G Benign ★★ same condition
GDNF c.*1264C>T Benign ★★ same condition
GDNF c.*1605T>C Benign ★★ same condition
GDNF c.*1651A>G Benign ★★ same condition
GDNF c.*2162G>T 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/gdnf-p-arg74 (accessed [today's date]).

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