Is FECH p.Arg215Trp (c.643C>T) pathogenic?

FECH p.Arg215Trp (c.643C>T) is classified Uncertain significance in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely benign (0.135); Ultra-rare (popmax 0.0164%, mid).

How common is FECH p.Arg215Trp (c.643C>T) in the general population?

FECH p.Arg215Trp (c.643C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about FECH p.Arg215Trp (c.643C>T)?

AlphaMissense predicts likely benign (score 0.135) — an in-silico prediction, not a clinical call.

FECH p.Arg215Trp

c.643C>T · rs746310270 · VCV2736738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.135	likely benign
REVEL	0.538	indeterminate
SaProt	LLR -11.43	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2, phastCons 0.071
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	20.9	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00143% 23/1,613,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00668%	14,974
Admixed American	0.00333%	29,991
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.0011%	90,771
South Asian	0.0011%	91,080

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: FECH
Protein: p.Arg215Trp
Coding: c.643C>T
MANE Select: NM_000140
dbSNP: rs746310270
Type: single nucleotide variant
Location: chr18:57562936 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB

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

Similar variants

FECH c.1137+3A>G Pathogenic/Likely pathogenic ★★ same type
FECH c.314+2T>G Pathogenic/Likely pathogenic ★★ same type
FECH c.463+1G>C Pathogenic ★★ same type
FECH c.598+1G>T Pathogenic ★★ same type
FECH c.599-2A>G Pathogenic ★★ same type
FECH c.913-2A>G Likely pathogenic ★★ same type
FECH p.Arg115Ter Pathogenic/Likely pathogenic ★★ same type
FECH p.Arg298Ter Pathogenic/Likely pathogenic ★★ 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/fech-p-arg215trp (accessed [today's date]).

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