Is PHYH p.Met154Val (c.460A>G) pathogenic?

PHYH p.Met154Val (c.460A>G) is classified Uncertain significance in PHYH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0773); Very rare (popmax 0.0011%, sas).

How common is PHYH p.Met154Val (c.460A>G) in the general population?

PHYH p.Met154Val (c.460A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PHYH p.Met154Val (c.460A>G)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

PHYH p.Met154Val

c.460A>G · rs959579723 · VCV1406047

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.96	GERP 0.52, phastCons 0.006
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.67 · regional, not allelic
Overall
CADD	16.64	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0011% South Asian · 1/91,032 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000559% 9/1,611,276 alleles · very rare exomes 9/1,459,280 · genomes 0/151,996 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,032
European (non-Finnish)	0.000679%	147,293

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.Met154Val
Coding: c.460A>G
MANE Select: NM_006214
dbSNP: rs959579723
Type: single nucleotide variant
Location: chr10:13291867 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB
Residue 154: a β-strand

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

Similar variants

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
PHYH p.Ala277Glu Pathogenic/Likely pathogenic ★★ same type
PHYH p.Arg275Gln 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-met154val (accessed [today's date]).

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