Is PHYH p.Arg329Pro (c.986G>C) pathogenic?

PHYH p.Arg329Pro (c.986G>C) is classified Uncertain significance in PHYH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-29). AlphaMissense: likely pathogenic (0.9508); Very rare (popmax 0.00133%, afr).

How common is PHYH p.Arg329Pro (c.986G>C) in the general population?

PHYH p.Arg329Pro (c.986G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PHYH p.Arg329Pro (c.986G>C)?

AlphaMissense predicts likely pathogenic (score 0.9508) — an in-silico prediction, not a clinical call.

PHYH p.Arg329Pro

c.986G>C · rs144085594 · VCV1461355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9508	likely pathogenic · top 6% in PHYH
REVEL	0.65	pathogenic-leaning
SaProt	LLR -13.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.54	GERP 0.58
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.67 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,006 alleles

Overall 0.000124% 2/1,612,576 alleles · very rare exomes 2/1,460,336 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,006
European (non-Finnish)	8.48e-05%	1,178,691

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.Arg329Pro
Coding: c.986G>C
MANE Select: NM_006214
dbSNP: rs144085594
Type: single nucleotide variant
Location: chr10:13278332 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB
Residue 329: a β-strand

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

Similar variants

PHYH p.Arg329Gln Uncertain significance ★★ ⚠ same residue
PHYH p.Arg329Ter Uncertain significance ★ same residue
PHYH c.134+1G>A Likely pathogenic ★★ same type
PHYH c.135-1G>C Pathogenic/Likely pathogenic ★★ same type
PHYH c.135-2A>G Pathogenic ★★ same type
PHYH c.497-1G>A Likely pathogenic ★★ same type
PHYH c.497-2A>G Pathogenic/Likely pathogenic ★★ same type
PHYH c.678+2T>C Likely 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/phyh-p-arg329pro (accessed [today's date]).

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