Is PHYKPL p.Arg17Trp (c.49C>T) pathogenic?

PHYKPL p.Arg17Trp (c.49C>T) is classified Uncertain significance in PHYKPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-24). AlphaMissense: ambiguous (0.4003); Ultra-rare (popmax 0.0289%, nfe).

How common is PHYKPL p.Arg17Trp (c.49C>T) in the general population?

PHYKPL p.Arg17Trp (c.49C>T) is ultra-rare (popmax 0.0289%, nfe) (gnomAD).

What do computational predictors say about PHYKPL p.Arg17Trp (c.49C>T)?

AlphaMissense predicts ambiguous (score 0.4003) — an in-silico prediction, not a clinical call.

PHYKPL p.Arg17Trp

c.49C>T · rs764678839 · VCV3212498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4003 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0289%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4003	ambiguous
REVEL	0.213	benign-leaning
SaProt	LLR -13.75	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -0.31, phastCons 0.6
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0047 · regional, not allelic
Overall
CADD	25.0	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 0.0289% European (non-Finnish) · 305/1,054,326 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0252%

Overall 0.0235% 315/1,341,284 alleles · ultra-rare exomes 300/1,190,696 · genomes 15/150,588 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0289%	3,457
Remaining individualsnot grpmax-eligible	0.00798%	12,534
Finnishnot grpmax-eligible	0.00523%	19,106
African / African-American	0.00465%	21,490
Admixed American	0.00403%	24,786

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: PHYKPL
Protein: p.Arg17Trp
Coding: c.49C>T
MANE Select: NM_153373
dbSNP: rs764678839
Type: single nucleotide variant
Location: chr5:178232502 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.20

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

Similar variants

PHYKPL p.Glu437Val Uncertain significance ★★ ⚠ same type
PHYKPL p.Ala139Val Uncertain significance ★ ⚠ same type
PHYKPL p.Ala168Val Uncertain significance ★ ⚠ same type
PHYKPL p.Ala318Thr Uncertain significance ★ ⚠ same type
PHYKPL p.Ala386Ser Uncertain significance ★ ⚠ same type
PHYKPL p.Ala3Pro Uncertain significance ★ ⚠ same type
PHYKPL p.Arg125Cys Uncertain significance ★ ⚠ same type
PHYKPL p.Arg125His 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/phykpl-p-arg17trp (accessed [today's date]).

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