Is PHYH p.Arg327Ter (c.979C>T) pathogenic?

PHYH p.Arg327Ter (c.979C>T) is classified Uncertain significance in PHYH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-11). Very rare (popmax 0.005%, amr).

How common is PHYH p.Arg327Ter (c.979C>T) in the general population?

PHYH p.Arg327Ter (c.979C>T) is very rare (popmax 0.005%, amr) (gnomAD).

PHYH p.Arg327Ter

c.979C>T · rs546257524 · VCV2161212

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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
NMD	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.28	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -0.19	GERP 1.6
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

Grpmax group 0.005% Admixed American · 3/59,986 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000683% 11/1,611,422 alleles · very rare exomes 10/1,459,294 · genomes 1/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
African / African-American	0.00401%	24,959
East Asian	0.00223%	44,840
Remaining individualsnot grpmax-eligible	0.0016%	62,398
European (non-Finnish)	0.000255%	392,582

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.Arg327Ter
Coding: c.979C>T
MANE Select: NM_006214
dbSNP: rs546257524
Type: single nucleotide variant
Location: chr10:13278339 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB
Residue 327: an α-helix

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

Similar variants

PHYH p.Arg327Gln Likely benign ★★ ⚠ same residue
PHYH p.Arg327Leu Uncertain significance ★ ⚠ same residue
PHYH p.Arg327= Likely benign ★ 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

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-arg327ter (accessed [today's date]).

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