Is PRLR p.Val256Met (c.766G>A) pathogenic?

PRLR p.Val256Met (c.766G>A) is classified Uncertain significance in PRLR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-24). AlphaMissense: likely benign (0.1082); Ultra-rare (popmax 0.0589%, afr).

How common is PRLR p.Val256Met (c.766G>A) in the general population?

PRLR p.Val256Met (c.766G>A) is ultra-rare (popmax 0.0589%, afr) (gnomAD).

What do computational predictors say about PRLR p.Val256Met (c.766G>A)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

PRLR p.Val256Met

c.766G>A · rs151203148 · VCV2435252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0589%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -5.93	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 0.8	GERP 0.97, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 5,076 bp · p 0.31 · regional, not allelic
Overall
CADD	15.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0589% African / African-American · 44/74,724 alleles

Filtering AF 0.045% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0402%

Overall 0.00373% 60/1,609,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0589%	1,698
Middle Eastern	0.0165%	6,058
Admixed American	0.0133%	7,496
Remaining individualsnot grpmax-eligible	0.00641%	15,591
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
European (non-Finnish)	0.00017%	588,228

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.Val256Met
Coding: c.766G>A
MANE Select: NM_000949
dbSNP: rs151203148
Type: single nucleotide variant
Location: chr5:35068798 (GRCh38)
Gene constraint: LOEUF 0.438 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.67 · 12 PDB
Residue 256: a turn

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

Similar variants

PRLR p.Val256Ala Uncertain significance ★ ⚠ same residue
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

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-val256met (accessed [today's date]).

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