Is PHEX p.Cys59Ter (c.177C>A) pathogenic?

PHEX p.Cys59Ter (c.177C>A) is classified Pathogenic in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-06). No allele count reported in gnomAD v4.1 (AN 1,176,926).

How common is PHEX p.Cys59Ter (c.177C>A) in the general population?

PHEX p.Cys59Ter (c.177C>A) is no allele count reported in gnomAD v4.1 (AN 1,176,926) (gnomAD).

PHEX p.Cys59Ter

c.177C>A · rs2146979567 · VCV1074167

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,176,926)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -0.055, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,176,926). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHEX
Protein: p.Cys59Ter
Coding: c.177C>A
MANE Select: NM_000444
dbSNP: rs2146979567
Type: single nucleotide variant
Location: chrX:22038527 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 59: a disulfide bond; the peptidase m13 domain

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

Similar variants

PHEX p.Cys59Phe Uncertain significance ★ ⚠ same residue
PHEX p.Cys59Ser Likely pathogenic same residue
PHEX c.1079+1G>A Pathogenic ★★ same type
PHEX c.1079+2T>G Pathogenic ★★ same type
PHEX c.1080-1G>A Pathogenic ★★ same type
PHEX c.1080-2A>G Pathogenic ★★ same type
PHEX c.1080-3C>G Pathogenic ★★ same type
PHEX c.1173+1G>A Pathogenic ★★ 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/phex-p-cys59ter (accessed [today's date]).

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