Is PRLR p.Leu26= (c.78A>G) pathogenic?

PRLR p.Leu26= (c.78A>G) is classified Likely benign in PRLR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). Ultra-rare (popmax 0.0341%, mid).

How common is PRLR p.Leu26= (c.78A>G) in the general population?

PRLR p.Leu26= (c.78A>G) is ultra-rare (popmax 0.0341%, mid) (gnomAD).

PRLR p.Leu26=

c.78A>G · VCV4969851

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0341%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.44	GERP -2.2, phastCons 0.2
Overall
CADD	4.744	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0341% Middle Eastern · 2/5,860 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00918%

Overall 0.00211% 34/1,613,218 alleles · ultra-rare exomes 28/1,461,194 · genomes 6/152,024 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0341%	2,930
East Asian	0.0223%	4,481
Finnishnot grpmax-eligible	0.00625%	15,987
European (non-Finnish)	0.00153%	65,539

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.Leu26=
Coding: c.78A>G
MANE Select: NM_000949
Type: single nucleotide variant
Location: chr5:35086333 (GRCh38)
Gene constraint: LOEUF 0.438 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.67 · 12 PDB
Residue 26: an α-helix

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-leu26 (accessed [today's date]).

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