Is FERMT1 p.Arg554Trp (c.1660C>T) pathogenic?

FERMT1 p.Arg554Trp (c.1660C>T) is classified Uncertain significance in FERMT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-25). AlphaMissense: likely benign (0.2136); Very rare (popmax 0.00834%, amr); Associated with Inborn genetic diseases.

What condition is associated with FERMT1 p.Arg554Trp (c.1660C>T)?

FERMT1 p.Arg554Trp (c.1660C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FERMT1 p.Arg554Trp (c.1660C>T) in the general population?

FERMT1 p.Arg554Trp (c.1660C>T) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about FERMT1 p.Arg554Trp (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.2136) — an in-silico prediction, not a clinical call.

FERMT1 p.Arg554Trp

c.1660C>T · rs149523994 · VCV1500466

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2136	likely benign
REVEL	0.687	pathogenic-leaning
SaProt	LLR -11.52	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.21, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 42 kb · p 3.8e-05 · regional, not allelic
Overall
CADD	29.8	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

Grpmax group 0.00834% Admixed American · 5/59,954 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.0044% 71/1,613,810 alleles · very rare exomes 62/1,461,566 · genomes 9/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,991
African / African-American	0.00801%	12,490
European (non-Finnish)	0.00483%	20,701
Remaining individualsnot grpmax-eligible	0.0048%	20,827

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: FERMT1
Protein: p.Arg554Trp
Coding: c.1660C>T
MANE Select: NM_017671
dbSNP: rs149523994
Type: single nucleotide variant
Location: chr20:6084098 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14
Residue 554: the ferm domain

Full FERMT1 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

FERMT1 p.Arg554Gln Uncertain significance ★★ ⚠ same residue
FERMT1 p.Ala345Val Uncertain significance ★★ ⚠ same condition
FERMT1 p.Ala359Val Uncertain significance ★★ ⚠ same condition
FERMT1 p.Ala539Val Uncertain significance ★★ ⚠ same condition
FERMT1 p.Arg108Thr Uncertain significance ★★ ⚠ same condition
FERMT1 p.Arg17His Uncertain significance ★★ ⚠ same condition
FERMT1 p.Arg255His Uncertain significance ★★ ⚠ same condition
FERMT1 p.Arg522Trp 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/fermt1-p-arg554trp (accessed [today's date]).

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