Is PHYH p.Arg245Trp (c.733C>T) pathogenic?

PHYH p.Arg245Trp (c.733C>T) is classified Uncertain significance in PHYH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1368); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with PHYH p.Arg245Trp (c.733C>T)?

PHYH p.Arg245Trp (c.733C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHYH p.Arg245Trp (c.733C>T) in the general population?

PHYH p.Arg245Trp (c.733C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PHYH p.Arg245Trp (c.733C>T)?

AlphaMissense predicts likely benign (score 0.1368) — an in-silico prediction, not a clinical call.

PHYH p.Arg245Trp

c.733C>T · rs753737115 · VCV1922339

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1368 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1368	likely benign
REVEL	0.55	indeterminate
SaProt	LLR -8.51	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 1.3	GERP 1.7, phastCons 0.001
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.67 · regional, not allelic
Overall
CADD	22.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00105% 17/1,613,684 alleles · ultra-rare exomes 15/1,461,676 · genomes 2/152,008 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00329%	30,354
Admixed American	0.00167%	59,964
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00134%	74,886
European (non-Finnish)	0.000848%	117,982

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.Arg245Trp
Coding: c.733C>T
MANE Select: NM_006214
dbSNP: rs753737115
Type: single nucleotide variant
Location: chr10:13283785 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB
Residue 245: a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHYH p.Arg245Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PHYH p.Arg245= Likely benign ★ same residue
PHYH p.Ala192Ser Uncertain significance ★★ ⚠ same condition
PHYH p.Ala244Gly Uncertain significance ★★ ⚠ same condition
PHYH p.Ala283Thr Uncertain significance ★★ same condition
PHYH p.Arg80Cys Uncertain significance ★★ ⚠ same condition
PHYH p.Asp77Asn Uncertain significance ★★ ⚠ same condition
PHYH p.Gln42Arg Uncertain significance ★★ ⚠ 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-arg245trp (accessed [today's date]).

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