Is FRMD5 p.Ser375Phe (c.1124C>T) pathogenic?

FRMD5 p.Ser375Phe (c.1124C>T) is classified Likely pathogenic in FRMD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.9888); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with eye movement abnormalities and ataxia.

What condition is associated with FRMD5 p.Ser375Phe (c.1124C>T)?

FRMD5 p.Ser375Phe (c.1124C>T) is associated with neurodevelopmental disorder with eye movement abnormalities and ataxia (ClinVar).

How common is FRMD5 p.Ser375Phe (c.1124C>T) in the general population?

FRMD5 p.Ser375Phe (c.1124C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FRMD5 p.Ser375Phe (c.1124C>T)?

AlphaMissense predicts likely pathogenic (score 0.9888) — an in-silico prediction, not a clinical call.

FRMD5 p.Ser375Phe

c.1124C>T · VCV4531500

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9888 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with eye movement abnormalities and ataxia

Computational evidence

Protein change
AlphaMissense	0.9888	likely pathogenic ✓ concordant with ClinVar
REVEL	0.703	pathogenic-leaning
SaProt	LLR -10.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 31 kb · p 3.2e-08 · regional, not allelic
Overall
CADD	27.8	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: FRMD5
Protein: p.Ser375Phe
Coding: c.1124C>T
MANE Select: NM_032892
Type: single nucleotide variant
Location: chr15:43883714 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 75.79
Residue 375: a modified residue (phosphoserine)

Full FRMD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with eye movement abnormalities and ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FRMD5 p.Arg553Thr Uncertain significance ★★ ⚠ same condition
FRMD5 p.Glu169Lys Uncertain significance ★★ ⚠ same condition
FRMD5 p.Ser351Asn Likely pathogenic ★ same condition
FRMD5 p.Cys352Arg Uncertain significance ★ ⚠ same condition
FRMD5 p.Gln40His Uncertain significance ★ same condition
FRMD5 p.Gly358Asp Uncertain significance ★ ⚠ same condition
FRMD5 p.Leu232Val Uncertain significance ★ ⚠ same condition
FRMD5 p.Lys95Asn 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/frmd5-p-ser375phe (accessed [today's date]).

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