Is FER p.Thr628Ile (c.1883C>T) pathogenic?

FER p.Thr628Ile (c.1883C>T) is classified Uncertain significance in FER (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). AlphaMissense: likely pathogenic (0.8444); Very rare (popmax 8.49e-05%, nfe); Associated with Duane retraction syndrome.

What condition is associated with FER p.Thr628Ile (c.1883C>T)?

FER p.Thr628Ile (c.1883C>T) is associated with Duane retraction syndrome (ClinVar).

How common is FER p.Thr628Ile (c.1883C>T) in the general population?

FER p.Thr628Ile (c.1883C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about FER p.Thr628Ile (c.1883C>T)?

AlphaMissense predicts likely pathogenic (score 0.8444) — an in-silico prediction, not a clinical call.

FER p.Thr628Ile

c.1883C>T · rs2534099165 · VCV3024397

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8444 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Duane retraction syndrome

Computational evidence

Protein change
AlphaMissense	0.8444	likely pathogenic
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -6.34	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 302 kb · p 0.76 · regional, not allelic
Overall
CADD	26.9	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 8.49e-05% European (non-Finnish) · 1/1,177,446 alleles

Overall 0.000124% 2/1,608,976 alleles · very rare exomes 2/1,456,744 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,952
European (non-Finnish)grpmax	8.49e-05%	1,177,446

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FER
Protein: p.Thr628Ile
Coding: c.1883C>T
MANE Select: NM_005246
dbSNP: rs2534099165
Type: single nucleotide variant
Location: chr5:109047157 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.29 · 2 PDB
Residue 628: the protein kinase domain

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

Disease context

Duane retraction syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FER p.Gln629His Uncertain significance ★ ⚠ same condition
FER p.Ala272Thr Uncertain significance ★ ⚠ same type
FER p.Ala313Gly Uncertain significance ★ ⚠ same type
FER p.Ala438Ser Uncertain significance ★ ⚠ same type
FER p.Ala89Thr Uncertain significance ★ ⚠ same type
FER p.Arg417Ser Uncertain significance ★ ⚠ same type
FER p.Arg707His Uncertain significance ★ ⚠ same type
FER p.Asn148Ile Uncertain significance ★ ⚠ 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/fer-p-thr628ile (accessed [today's date]).

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