Is PHYH p.Phe131Val (c.391T>G) pathogenic?

PHYH p.Phe131Val (c.391T>G) is classified Uncertain significance in PHYH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.7588); Ultra-rare (popmax 0.0367%, amr); Associated with Inborn genetic diseases.

What condition is associated with PHYH p.Phe131Val (c.391T>G)?

PHYH p.Phe131Val (c.391T>G) is associated with Inborn genetic diseases (ClinVar).

How common is PHYH p.Phe131Val (c.391T>G) in the general population?

PHYH p.Phe131Val (c.391T>G) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about PHYH p.Phe131Val (c.391T>G)?

AlphaMissense predicts likely pathogenic (score 0.7588) — an in-silico prediction, not a clinical call.

PHYH p.Phe131Val

c.391T>G · VCV3931920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7588 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7588	likely pathogenic
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 0.35, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.67 · regional, not allelic
Overall
CADD	27.9	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 0.0367% Admixed American · 22/59,996 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00143% 23/1,613,882 alleles · ultra-rare exomes 3/1,461,718 · genomes 20/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,727
European (non-Finnish)	8.48e-05%	1,179,898

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.Phe131Val
Coding: c.391T>G
MANE Select: NM_006214
Type: single nucleotide variant
Location: chr10:13294451 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB
Residue 131: an α-helix

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.Ala192Ser Uncertain significance ★★ ⚠ same condition
PHYH p.Ala244Gly Uncertain significance ★★ ⚠ same condition
PHYH p.Ala283Thr Uncertain significance ★★ same condition
PHYH p.Arg245Trp 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
PHYH p.Glu241Gly 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-phe131val (accessed [today's date]).

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