Is RET p.Arg77Cys (c.229C>T) pathogenic?

RET p.Arg77Cys (c.229C>T) is classified Pathogenic/Likely pathogenic in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-25). AlphaMissense: likely benign (0.1252); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Arg77Cys (c.229C>T)?

RET p.Arg77Cys (c.229C>T) is associated with multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Arg77Cys (c.229C>T) in the general population?

RET p.Arg77Cys (c.229C>T) is absent from gnomAD v4.1 (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RET p.Arg77Cys (c.229C>T)?

AlphaMissense predicts likely benign (score 0.1252) — an in-silico prediction, not a clinical call.

RET p.Arg77Cys

c.229C>T · rs1588862595 · VCV1069381

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1252 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.1252	likely benign ⚠ discordant with ClinVar
REVEL	0.476	indeterminate
SaProt	LLR -9.68	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 2.4	GERP 0.58, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 1,972 bp · p 4.9e-10 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RET
Protein: p.Arg77Cys
Coding: c.229C>T
MANE Select: NM_020975
dbSNP: rs1588862595
Type: single nucleotide variant
Location: chr10:43100614 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 77: an α-helix; a UniProt-annotated variant site (in hscr1); the 'cadherin-like region 1 (cld1)' region

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

Disease context

multiple endocrine neoplasia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Arg77Gly Uncertain significance ★★ ⚠ same residue
RET p.Arg77= Likely benign ★★ same residue
RET p.Arg77His Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Arg77Ser Uncertain significance ★ ⚠ same residue
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg897Ter Pathogenic ★★ same condition
RET p.Asp631Tyr 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-arg77cys (accessed [today's date]).

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