Is PRLR p.Pro153Leu (c.458C>T) pathogenic?

PRLR p.Pro153Leu (c.458C>T) is classified Uncertain significance in PRLR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-13). AlphaMissense: likely benign (0.2164); Very rare (popmax 0.0022%, sas).

How common is PRLR p.Pro153Leu (c.458C>T) in the general population?

PRLR p.Pro153Leu (c.458C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PRLR p.Pro153Leu (c.458C>T)?

AlphaMissense predicts likely benign (score 0.2164) — an in-silico prediction, not a clinical call.

PRLR p.Pro153Leu

c.458C>T · rs1372978753 · VCV2560006

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2164	likely benign
REVEL	0.559	indeterminate
SaProt	LLR -10.93	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 19 kb · p 0.00022 · regional, not allelic
Overall
CADD	27.6	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 0.0022% South Asian · 2/91,076 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,858 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: PRLR
Protein: p.Pro153Leu
Coding: c.458C>T
MANE Select: NM_000949
dbSNP: rs1372978753
Type: single nucleotide variant
Location: chr5:35072660 (GRCh38)
Gene constraint: LOEUF 0.438 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.67 · 12 PDB
Residue 153: the fibronectin type-iii 2 domain

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

Similar variants

PRLR p.Glu485Ala Uncertain significance ★★ ⚠ same type
PRLR p.Ile79Val Uncertain significance ★★ ⚠ same type
PRLR p.Thr490Met Uncertain significance ★★ ⚠ same type
PRLR c.685+7G>A Benign ★★ same type
PRLR p.Glu470= Benign ★★ same type
PRLR p.Leu284Trp Likely pathogenic ★ ⚠ same type
PRLR p.Ala185Ser Uncertain significance ★ ⚠ same type
PRLR p.Ala221Val Uncertain significance ★ ⚠ same type

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/prlr-p-pro153leu (accessed [today's date]).

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