Is RET p.Phe147Ser (c.440T>C) pathogenic?

RET p.Phe147Ser (c.440T>C) is classified Likely pathogenic in RET (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-01-01). AlphaMissense: likely pathogenic (0.8548); Very rare (popmax 6.2e-05%); Associated with Hirschsprung disease.

What condition is associated with RET p.Phe147Ser (c.440T>C)?

RET p.Phe147Ser (c.440T>C) is associated with Hirschsprung disease (ClinVar).

How common is RET p.Phe147Ser (c.440T>C) in the general population?

RET p.Phe147Ser (c.440T>C) is very rare (popmax 6.2e-05%) (gnomAD).

How is Hirschsprung disease inherited?

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

What do computational predictors say about RET p.Phe147Ser (c.440T>C)?

AlphaMissense predicts likely pathogenic (score 0.8548) — an in-silico prediction, not a clinical call.

RET p.Phe147Ser

c.440T>C · rs1564490097 · VCV599631

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hirschsprung disease

Computational evidence

Protein change
AlphaMissense	0.8548	likely pathogenic ✓ concordant with ClinVar
REVEL	0.555	indeterminate
SaProt	LLR -12.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	26.5	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 6.2e-05%

Overall 6.2e-05% 1/1,614,148 alleles · very rare exomes 1/1,461,894 · genomes 0/152,254 · joint denominator

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.Phe147Ser
Coding: c.440T>C
MANE Select: NM_020975
dbSNP: rs1564490097
Type: single nucleotide variant
Location: chr10:43102444 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 147: a β-strand; the 'cadherin-like region 1 (cld1)' region

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

Disease context

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

For Hirschsprung disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Multigenic/multifactorial
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

RET p.Cys609Arg Pathogenic ★★ same condition
RET p.Cys611Arg Pathogenic/Likely pathogenic ★★ same condition
RET p.Cys620Arg Pathogenic ★★ same condition
RET p.Cys620Gly Pathogenic ★★ same condition
RET p.Cys620Tyr Pathogenic ★★ same condition
RET p.Ser32Leu Likely pathogenic ★★ ⚠ same condition
RET p.Arg813Trp Uncertain significance ★★ ⚠ same condition
RET p.Met1064Thr Uncertain significance ★★ ⚠ 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-phe147ser (accessed [today's date]).

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