Is FECH p.Arg164Gln (c.491G>A) pathogenic?

FECH p.Arg164Gln (c.491G>A) is classified Uncertain significance in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.9197); Very rare (popmax 0.00549%, sas).

How common is FECH p.Arg164Gln (c.491G>A) in the general population?

FECH p.Arg164Gln (c.491G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about FECH p.Arg164Gln (c.491G>A)?

AlphaMissense predicts likely pathogenic (score 0.9197) — an in-silico prediction, not a clinical call.

FECH p.Arg164Gln

c.491G>A · VCV4749272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9197	likely pathogenic
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Pangolin	Δ0.41	gain · loss 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	34.0	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 0.00549% South Asian · 5/91,088 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000744% 12/1,613,936 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,218
Remaining individualsnot grpmax-eligible	0.0032%	31,244
East Asian	0.00223%	44,894
African / African-American	0.00134%	74,870
European (non-Finnish)	0.000254%	393,332

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.Arg164Gln
Coding: c.491G>A
MANE Select: NM_000140
Type: single nucleotide variant
Location: chr18:57566554 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 164: a β-strand

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

Similar variants

FECH p.Arg164Trp Uncertain significance ★ ⚠ 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-arg164gln (accessed [today's date]).

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