Is PRLR p.Arg66Lys (c.197G>A) pathogenic?

PRLR p.Arg66Lys (c.197G>A) is classified Likely benign in PRLR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.000254%, nfe).

How common is PRLR p.Arg66Lys (c.197G>A) in the general population?

PRLR p.Arg66Lys (c.197G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PRLR p.Arg66Lys (c.197G>A)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

PRLR p.Arg66Lys

c.197G>A · VCV3425504

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -3.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -3.7, phastCons 0.91
Regional constraint	o/e 0.76	unconstrained · MANE · 19 kb · p 0.00022 · regional, not allelic
Overall
CADD	4.461	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 0.000254% European (non-Finnish) · 3/1,179,900 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,886 alleles · very rare exomes 3/1,461,646 · genomes 0/152,240 · 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: PRLR
Protein: p.Arg66Lys
Coding: c.197G>A
MANE Select: NM_000949
Type: single nucleotide variant
Location: chr5:35086214 (GRCh38)
Gene constraint: LOEUF 0.438 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.67 · 12 PDB
Residue 66: a β-strand; the fibronectin type-iii 1 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-arg66lys (accessed [today's date]).

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