Is GDNF p.Arg91Gln (c.272G>A) pathogenic?

GDNF p.Arg91Gln (c.272G>A) is classified Uncertain significance in GDNF (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-28). AlphaMissense: likely benign (0.1065); Ultra-rare (popmax 0.0329%, mid); Associated with Hirschsprung disease, susceptibility to, 3.

What condition is associated with GDNF p.Arg91Gln (c.272G>A)?

GDNF p.Arg91Gln (c.272G>A) is associated with Hirschsprung disease, susceptibility to, 3 (ClinVar).

How common is GDNF p.Arg91Gln (c.272G>A) in the general population?

GDNF p.Arg91Gln (c.272G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about GDNF p.Arg91Gln (c.272G>A)?

AlphaMissense predicts likely benign (score 0.1065) — an in-silico prediction, not a clinical call.

GDNF p.Arg91Gln

c.272G>A · rs769492137 · VCV906139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hirschsprung disease, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.1065	likely benign
REVEL	0.485	indeterminate
SaProt	LLR -7.48	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 6	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 19 kb · p 0.087 · regional, not allelic
Overall
CADD	24.8	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00279% 45/1,613,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
East Asian	0.0111%	8,978
European (non-Finnish)	0.00305%	32,771
Finnishnot grpmax-eligible	0.00156%	64,042
South Asian	0.0011%	91,074

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.Arg91Gln
Coding: c.272G>A
MANE Select: NM_000514
dbSNP: rs769492137
Type: single nucleotide variant
Location: chr5:37816015 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 75.29 · 4 PDB
Residue 91: the 'disordered' region

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-arg91gln (accessed [today's date]).

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