Is RET p.Cys634Phe (c.1901G>T) pathogenic?

RET p.Cys634Phe (c.1901G>T) is classified Pathogenic in RET (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.5703); Very rare (popmax 0.00133%, afr); Associated with RET-related disorder.

What condition is associated with RET p.Cys634Phe (c.1901G>T)?

RET p.Cys634Phe (c.1901G>T) is associated with RET-related disorder, familial medullary thyroid carcinoma, pheochromocytoma (ClinVar).

How common is RET p.Cys634Phe (c.1901G>T) in the general population?

RET p.Cys634Phe (c.1901G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RET p.Cys634Phe (c.1901G>T)?

AlphaMissense predicts likely pathogenic (score 0.5703) — an in-silico prediction, not a clinical call.

RET p.Cys634Phe

c.1901G>T · rs75996173 · VCV13911

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.5703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RET-related disorder

Computational evidence

Protein change
AlphaMissense	0.5703	likely pathogenic ✓ concordant with ClinVar
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -12.95	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 12	GERP 0.66, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	28.1	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 0.00133% African / African-American · 1/74,970 alleles

Overall 6.87e-05% 1/1,455,706 alleles · very rare

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.Cys634Phe
Coding: c.1901G>T
MANE Select: NM_020975
dbSNP: rs75996173
Type: single nucleotide variant
Location: chr10:43114501 (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: familial medullary thyroid carcinoma pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Cys634Arg Pathogenic/Likely pathogenic ★★ same residue
RET p.Cys634Gly 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-cys634phe (accessed [today's date]).

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