Is SYP p.Phe75Val (c.223T>G) pathogenic?

SYP p.Phe75Val (c.223T>G) is classified Uncertain significance in SYP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely pathogenic (0.9974); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SYP p.Phe75Val (c.223T>G)?

SYP p.Phe75Val (c.223T>G) is associated with Inborn genetic diseases (ClinVar).

How common is SYP p.Phe75Val (c.223T>G) in the general population?

SYP p.Phe75Val (c.223T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYP p.Phe75Val (c.223T>G)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

SYP p.Phe75Val

c.223T>G · VCV3452126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic · top 4% in SYP
REVEL	0.723	pathogenic-leaning
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 6,874 bp · p 7.3e-06 · regional, not allelic
Overall
CADD	27.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SYP
Protein: p.Phe75Val
Coding: c.223T>G
MANE Select: NM_003179
Type: single nucleotide variant
Location: chrX:49197719 (GRCh38)
Structure: AlphaFold pLDDT 77.92
Residue 75: the marvel domain

Full SYP 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

SYP p.Gly254Asp Uncertain significance ★★ same condition
SYP p.Glu62Lys Likely benign ★★ same condition
SYP p.Asn135Ser Uncertain significance ★ ⚠ same condition
SYP p.Asp172Asn Uncertain significance ★ ⚠ same condition
SYP p.Glu174Lys Uncertain significance ★ ⚠ same condition
SYP p.Gly251Ser Uncertain significance ★ ⚠ same condition
SYP p.Gly290Arg Uncertain significance ★ ⚠ same condition
SYP p.Gly290Trp Conflicting classifications of pathogenicity ★ ⚠ 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/syp-p-phe75val (accessed [today's date]).

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