Is RET p.Pro384Arg (c.1151C>G) pathogenic?

RET p.Pro384Arg (c.1151C>G) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.119); Very rare (popmax 0.00329%, sas); Associated with central hypoventilation syndrome, congenital.

What condition is associated with RET p.Pro384Arg (c.1151C>G)?

RET p.Pro384Arg (c.1151C>G) is associated with central hypoventilation syndrome, congenital, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Pro384Arg (c.1151C>G) in the general population?

RET p.Pro384Arg (c.1151C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about RET p.Pro384Arg (c.1151C>G)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

RET p.Pro384Arg

c.1151C>G · rs771679592 · VCV405529

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

central hypoventilation syndrome, congenital

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -7.16	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 2.1	GERP 1.8, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	20.2	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 0.00329% South Asian · 3/91,088 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000682% 11/1,613,804 alleles · very rare exomes 9/1,461,630 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
African / African-American	0.00133%	74,908
European (non-Finnish)	0.000593%	168,577

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: RET
Protein: p.Pro384Arg
Coding: c.1151C>G
MANE Select: NM_020975
dbSNP: rs771679592
Type: single nucleotide variant
Location: chr10:43109118 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB

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

Disease context

central hypoventilation syndrome, congenital — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Pro384Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Pro384= Likely benign ★ same residue
RET p.Pro384fs Pathogenic ★ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg77Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
RET p.Arg873Trp 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/ret-p-pro384arg (accessed [today's date]).

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