Is RET p.Ala641Pro (c.1921G>C) pathogenic?

RET p.Ala641Pro (c.1921G>C) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-15). AlphaMissense: likely pathogenic (0.6784); Absent from gnomAD v4.1; Associated with familial medullary thyroid carcinoma.

What condition is associated with RET p.Ala641Pro (c.1921G>C)?

RET p.Ala641Pro (c.1921G>C) is associated with familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Ala641Pro (c.1921G>C) in the general population?

RET p.Ala641Pro (c.1921G>C) is absent from gnomAD v4.1 (gnomAD).

How is Isolated familial medullary thyroid carcinoma inherited?

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

What do computational predictors say about RET p.Ala641Pro (c.1921G>C)?

AlphaMissense predicts likely pathogenic (score 0.6784) — an in-silico prediction, not a clinical call.

RET p.Ala641Pro

c.1921G>C · rs377767411 · VCV1698934

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6784 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,609,224)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial medullary thyroid carcinoma

Computational evidence

Protein change
AlphaMissense	0.6784	likely pathogenic
REVEL	0.751	pathogenic-leaning
SaProt	LLR -12.99	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 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,609,224). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RET
Protein: p.Ala641Pro
Coding: c.1921G>C
MANE Select: NM_020975
dbSNP: rs377767411
Type: single nucleotide variant
Location: chr10:43114521 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 641: a UniProt-annotated variant site (in mtc; sporadic form)

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

Disease context

familial medullary thyroid carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated familial medullary thyroid carcinoma (Orphanet):

Inheritance: Autosomal dominant

Similar variants

RET p.Ala641Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Ala641Ser Uncertain significance ★★ ⚠ same residue
RET p.Ala641= Benign/Likely benign ★★ same residue
RET p.Cys609Arg Pathogenic ★★ same condition
RET p.Cys609Tyr Pathogenic ★★ same condition
RET p.Cys618Arg Pathogenic/Likely pathogenic ★★ same condition
RET p.Cys618Gly Pathogenic ★★ same condition
RET p.Cys618Ser 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-ala641pro (accessed [today's date]).

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