Is PHYH p.Ser31= (c.93A>C) pathogenic?

PHYH p.Ser31= (c.93A>C) is classified Uncertain significance in PHYH (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00446%, eas); Associated with adult Refsum disease.

What condition is associated with PHYH p.Ser31= (c.93A>C)?

PHYH p.Ser31= (c.93A>C) is associated with adult Refsum disease (ClinVar).

How common is PHYH p.Ser31= (c.93A>C) in the general population?

PHYH p.Ser31= (c.93A>C) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Adult Refsum disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PHYH p.Ser31=

c.93A>C · rs202198596 · VCV299261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

adult Refsum disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -2.8
Overall
CADD	5.496	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,834 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000125% 2/1,604,590 alleles · very rare exomes 1/1,452,302 · genomes 1/152,288 · 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.Ser31=
Coding: c.93A>C
MANE Select: NM_006214
dbSNP: rs202198596
Type: single nucleotide variant
Location: chr10:13298228 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB

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

Disease context

adult Refsum disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Adult Refsum disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PHYH c.134+1G>A Likely pathogenic ★★ same condition
PHYH c.135-1G>C Pathogenic/Likely pathogenic ★★ same condition
PHYH c.135-2A>G Pathogenic ★★ same condition
PHYH c.497-1G>A Likely pathogenic ★★ same condition
PHYH c.497-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHYH c.678+2T>C Likely pathogenic ★★ same condition
PHYH p.Ala277Glu Pathogenic/Likely pathogenic ★★ same condition
PHYH p.Arg275Gln 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-ser31 (accessed [today's date]).

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