Is PROKR2 p.Arg248Trp (c.742C>T) pathogenic?

PROKR2 p.Arg248Trp (c.742C>T) is classified Uncertain significance in PROKR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-20). AlphaMissense: likely benign (0.0903); Very rare (popmax 0.00445%, eas); Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Arg248Trp (c.742C>T)?

PROKR2 p.Arg248Trp (c.742C>T) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

How common is PROKR2 p.Arg248Trp (c.742C>T) in the general population?

PROKR2 p.Arg248Trp (c.742C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about PROKR2 p.Arg248Trp (c.742C>T)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

PROKR2 p.Arg248Trp

c.742C>T · rs483352766 · VCV100889

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypogonadotropic hypogonadism 3 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.444	indeterminate
SaProt	LLR -7.32	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 5.8	GERP -1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	26.6	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 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00118% 19/1,614,076 alleles · very rare exomes 13/1,461,882 · genomes 6/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
Admixed American	0.00333%	29,994
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00267%	37,466
Finnishnot grpmax-eligible	0.00156%	64,038
South Asian	0.0011%	91,080
European (non-Finnish)	0.000763%	131,117

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: PROKR2
Protein: p.Arg248Trp
Coding: c.742C>T
MANE Select: NM_144773
dbSNP: rs483352766
Type: single nucleotide variant
Location: chr20:5302453 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 248: a UniProt-annotated variant site (in hh3)

Full PROKR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 3 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROKR2 p.Arg248Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PROKR2 p.Arg164Gln Likely pathogenic ★★ same condition
PROKR2 p.Glu231Lys Likely pathogenic ★★ ⚠ same condition
PROKR2 p.Tyr316Ter Likely pathogenic ★★ same condition
PROKR2 p.Ala103Val Uncertain significance ★★ ⚠ same condition
PROKR2 p.Ala129Thr Uncertain significance ★★ ⚠ same condition
PROKR2 p.Ala156Thr Uncertain significance ★★ same condition
PROKR2 p.Arg135Cys Uncertain significance ★★ ⚠ same condition

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/prokr2-p-arg248trp (accessed [today's date]).

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