Is GDNF p.Arg116Gln (c.347G>A) pathogenic?

GDNF p.Arg116Gln (c.347G>A) is classified Uncertain significance in GDNF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: likely benign (0.1133); Ultra-rare (popmax 0.0379%, eas); Associated with Hirschsprung disease, susceptibility to, 3.

What condition is associated with GDNF p.Arg116Gln (c.347G>A)?

GDNF p.Arg116Gln (c.347G>A) is associated with Hirschsprung disease, susceptibility to, 3 (ClinVar).

How common is GDNF p.Arg116Gln (c.347G>A) in the general population?

GDNF p.Arg116Gln (c.347G>A) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about GDNF p.Arg116Gln (c.347G>A)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

GDNF p.Arg116Gln

c.347G>A · rs772460903 · VCV906137

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hirschsprung disease, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.354	indeterminate
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 19 kb · p 0.087 · regional, not allelic
Overall
CADD	22.8	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 0.0379% East Asian · 17/44,898 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00892% 144/1,614,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,641
European (non-Finnish)	0.00983%	10,173
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.00667%	15,001
African / African-American	0.00267%	37,462

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.Arg116Gln
Coding: c.347G>A
MANE Select: NM_000514
dbSNP: rs772460903
Type: single nucleotide variant
Location: chr5:37815940 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 75.29 · 4 PDB
Residue 116: a turn

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 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
GDNF c.*2204G>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-arg116gln (accessed [today's date]).

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