Is PHYH p.Pro29Ser (c.85C>T) pathogenic?

PHYH p.Pro29Ser (c.85C>T) is classified Benign in PHYH (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.075); Common (popmax 18%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with adult Refsum disease.

What condition is associated with PHYH p.Pro29Ser (c.85C>T)?

PHYH p.Pro29Ser (c.85C>T) is associated with adult Refsum disease (ClinVar).

How is Adult Refsum disease inherited?

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

What do computational predictors say about PHYH p.Pro29Ser (c.85C>T)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

PHYH p.Pro29Ser

Q: How common is PHYH p.Pro29Ser (c.85C>T) in the general population?

PHYH p.Pro29Ser (c.85C>T) is common (popmax 18%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.85C>T · rs28938169 · VCV7582

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

adult Refsum disease

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -5.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP 0.46
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.67 · regional, not allelic
Overall
CADD	13.64	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 18% European (non-Finnish) · 209,541/1,161,678 alleles

Filtering AF 18% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.9%

Overall 16.5% 263,679/1,593,910 alleles · common exomes 241,357/1,441,772 · genomes 22,322/152,138 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	22.8%	4
European (non-Finnish)grpmax	18%	6
Remaining individualsnot grpmax-eligible	15.2%	7
Ashkenazi Jewishnot grpmax-eligible	14.8%	7
African / African-American	11.7%	9
Admixed American	10.9%	9
Middle Eastern	10.4%	10
South Asian	10.1%	10
Amishnot grpmax-eligible	7.69%	13
East Asian	1.53%	66

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro29Ser
Coding: c.85C>T
MANE Select: NM_006214
dbSNP: rs28938169
Type: single nucleotide variant
Location: chr10:13298236 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB
Residue 29: a UniProt-annotated variant site (in)

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 p.Pro29= Likely benign ★ same residue
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

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-pro29ser (accessed [today's date]).

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