Is RET p.Ala877Pro (c.2629G>C) pathogenic?

RET p.Ala877Pro (c.2629G>C) is classified Likely pathogenic in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-24). AlphaMissense: likely pathogenic (0.9695); No allele count reported in gnomAD v4.1 (AN 1,613,976); Associated with Hirschsprung disease, susceptibility to, 1.

What condition is associated with RET p.Ala877Pro (c.2629G>C)?

RET p.Ala877Pro (c.2629G>C) is associated with Hirschsprung disease, susceptibility to, 1 (ClinVar).

How common is RET p.Ala877Pro (c.2629G>C) in the general population?

RET p.Ala877Pro (c.2629G>C) is no allele count reported in gnomAD v4.1 (AN 1,613,976) (gnomAD).

What do computational predictors say about RET p.Ala877Pro (c.2629G>C)?

AlphaMissense predicts likely pathogenic (score 0.9695) — an in-silico prediction, not a clinical call.

RET p.Ala877Pro

c.2629G>C · rs1838178869 · VCV870394

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9695 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,976)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hirschsprung disease, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.9695	likely pathogenic ✓ concordant with ClinVar · top 4% in RET
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -14.80	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 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 4,087 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	33.0	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

No allele count reported in gnomAD v4.1 (AN 1,613,976). 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.Ala877Pro
Coding: c.2629G>C
MANE Select: NM_020975
dbSNP: rs1838178869
Type: single nucleotide variant
Location: chr10:43120102 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 877: an α-helix; the protein kinase domain

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

Disease context

Hirschsprung disease, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RET p.Ala877Ser Uncertain significance ★★ ⚠ same residue
RET p.Ala877= Likely benign ★★ same residue
RET p.Ala877Val Uncertain significance ★ ⚠ same residue
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Arg897Gln Pathogenic ★★ ⚠ same condition
RET p.Cys609Tyr 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-ala877pro (accessed [today's date]).

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