Is RET p.Cys634Arg (c.1900T>C) pathogenic?

RET p.Cys634Arg (c.1900T>C) is classified Pathogenic/Likely pathogenic in RET (ClinVar, Multiple submitters, 27 submitters; last evaluated 2026-02-11). AlphaMissense: likely pathogenic (0.8173); Very rare (popmax 0.00334%, amr); Associated with RET-related disorder.

What condition is associated with RET p.Cys634Arg (c.1900T>C)?

RET p.Cys634Arg (c.1900T>C) is associated with RET-related disorder, Hirschsprung disease, susceptibility to, 1, multiple endocrine neoplasia type 2B (ClinVar).

How common is RET p.Cys634Arg (c.1900T>C) in the general population?

RET p.Cys634Arg (c.1900T>C) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about RET p.Cys634Arg (c.1900T>C)?

AlphaMissense predicts likely pathogenic (score 0.8173) — an in-silico prediction, not a clinical call.

RET p.Cys634Arg

c.1900T>C · rs75076352 · VCV13917

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 27 submitters

AlphaMissense

likely pathogenic

0.8173 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RET-related disorder

Computational evidence

Protein change
AlphaMissense	0.8173	likely pathogenic ✓ concordant with ClinVar
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -13.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.00334% Admixed American · 2/59,968 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000249% 4/1,607,602 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,984
East Asian	0.00223%	44,840
European (non-Finnish)	8.47e-05%	1,179,970

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.Cys634Arg
Coding: c.1900T>C
MANE Select: NM_020975
dbSNP: rs75076352
Type: single nucleotide variant
Location: chr10:43114500 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 634: a UniProt-annotated variant site (in men2a); a UniProt-annotated variant site (in men2a and pheochromocytoma); a UniProt-annotated variant site (in men2a, pheochromocytoma and mtc; familial form; also found as somatic mutation in a sporadic thyroid carcinoma); a UniProt-annotated variant site (in men2a, pheochromocytoma and mtc; familial form); a disulfide bond

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

Disease context

RET-related disorder

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

Similar variants

RET p.Cys634Gly Pathogenic ★★ same residue
RET p.Cys634Phe Pathogenic ★★ same residue
RET p.Cys634Ser Pathogenic ★★ same residue
RET p.Cys634Trp Pathogenic ★★ same residue
RET p.Cys634Tyr Pathogenic/Likely pathogenic ★★ same residue
RET p.Cys634Leu Pathogenic/Likely pathogenic ★★ same residue
RET p.Cys634_Arg635delinsTrpGly Pathogenic ★ same residue
RET c.1759+1G>A Pathogenic/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-cys634arg (accessed [today's date]).

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