Is PHYH p.Pro173Thr (c.517C>A) pathogenic?

PHYH p.Pro173Thr (c.517C>A) is classified Conflicting classifications of pathogenicity in PHYH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-25). AlphaMissense: likely pathogenic (0.8936); Very rare (popmax 0.000169%, nfe); Associated with PHYH-related disorder.

What condition is associated with PHYH p.Pro173Thr (c.517C>A)?

PHYH p.Pro173Thr (c.517C>A) is associated with PHYH-related disorder (ClinVar).

How common is PHYH p.Pro173Thr (c.517C>A) in the general population?

PHYH p.Pro173Thr (c.517C>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about PHYH p.Pro173Thr (c.517C>A)?

AlphaMissense predicts likely pathogenic (score 0.8936) — an in-silico prediction, not a clinical call.

PHYH p.Pro173Thr

c.517C>A · rs1835617888 · VCV866619

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHYH-related disorder

Computational evidence

Protein change
AlphaMissense	0.8936	likely pathogenic
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -14.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.67 · regional, not allelic
Overall
CADD	26.8	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 0.000169% European (non-Finnish) · 2/1,180,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,116 alleles · very rare exomes 2/1,461,842 · genomes 0/152,274 · joint denominator

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: PHYH
Protein: p.Pro173Thr
Coding: c.517C>A
MANE Select: NM_006214
dbSNP: rs1835617888
Type: single nucleotide variant
Location: chr10:13288521 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB
Residue 173: a UniProt-annotated variant site (in rd)

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

Disease context

PHYH-related disorder

Similar variants

PHYH p.Pro173Ser Uncertain significance ★ ⚠ same residue
PHYH p.Pro173= Likely benign ★ same residue
PHYH c.135-2A>G Pathogenic ★★ same condition
PHYH c.497-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHYH p.Ala277Glu Pathogenic/Likely pathogenic ★★ same condition
PHYH p.Arg275Gln Pathogenic/Likely pathogenic ★★ same condition
PHYH p.Arg275Trp Pathogenic/Likely pathogenic ★★ same condition
PHYH p.Gln237Ter Pathogenic/Likely pathogenic ★★ 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/phyh-p-pro173thr (accessed [today's date]).

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