Is PRLR p.Ala295Val (c.884C>T) pathogenic?

PRLR p.Ala295Val (c.884C>T) is classified Uncertain significance in PRLR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-21). AlphaMissense: likely benign (0.1671); Ultra-rare (popmax 0.0593%, sas).

How common is PRLR p.Ala295Val (c.884C>T) in the general population?

PRLR p.Ala295Val (c.884C>T) is ultra-rare (popmax 0.0593%, sas) (gnomAD).

What do computational predictors say about PRLR p.Ala295Val (c.884C>T)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

PRLR p.Ala295Val

c.884C>T · rs565387396 · VCV2341209

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0593%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.477	indeterminate
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 5,076 bp · p 0.31 · regional, not allelic
Overall
CADD	25.1	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 0.0593% South Asian · 54/91,060 alleles

Filtering AF 0.0466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0421%

Overall 0.00378% 61/1,613,930 alleles · ultra-rare exomes 55/1,461,666 · genomes 6/152,264 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0593%	1,686
Middle Eastern	0.0167%	5,998
Remaining individualsnot grpmax-eligible	0.0048%	20,831
European (non-Finnish)	0.000254%	393,307

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.Ala295Val
Coding: c.884C>T
MANE Select: NM_000949
dbSNP: rs565387396
Type: single nucleotide variant
Location: chr5:35066074 (GRCh38)
Gene constraint: LOEUF 0.438 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.67 · 12 PDB

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-ala295val (accessed [today's date]).

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