Is FECH p.Arg96Gln (c.287G>A) pathogenic?

FECH p.Arg96Gln (c.287G>A) is classified Benign in FECH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0919); Common (popmax 15.7%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about FECH p.Arg96Gln (c.287G>A)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

FECH p.Arg96Gln

Q: How common is FECH p.Arg96Gln (c.287G>A) in the general population?

FECH p.Arg96Gln (c.287G>A) is common (popmax 15.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.287G>A · rs1041951 · VCV327434

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.7%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.54	GERP 1.9, phastCons 0.082
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	20.6	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 15.7% European (non-Finnish) · 185,064/1,178,092 alleles

Filtering AF 15.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.6%

Overall 13.3% 214,230/1,612,052 alleles · common exomes 198,147/1,459,828 · genomes 16,083/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	15.7%	6
Ashkenazi Jewishnot grpmax-eligible	12.4%	8
Remaining individualsnot grpmax-eligible	12.4%	8
Finnishnot grpmax-eligible	10.2%	10
Admixed American	6.81%	15
Middle Eastern	5.68%	18
African / African-American	5.53%	18
Amishnot grpmax-eligible	5.27%	19
South Asian	2.81%	36
East Asian	0.049%	2,040

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.Arg96Gln
Coding: c.287G>A
MANE Select: NM_000140
dbSNP: rs1041951
Type: single nucleotide variant
Location: chr18:57573273 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 96: a UniProt-annotated variant site (in); a turn

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

Similar variants

FECH p.Arg96Ter Pathogenic/Likely pathogenic ★★ same residue
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

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-arg96gln (accessed [today's date]).

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