Is FER p.Thr164Pro (c.490A>C) pathogenic?

FER p.Thr164Pro (c.490A>C) is classified Uncertain significance in FER (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-22). AlphaMissense: likely benign (0.077); Ultra-rare (popmax 0.0992%, mid).

How common is FER p.Thr164Pro (c.490A>C) in the general population?

FER p.Thr164Pro (c.490A>C) is ultra-rare (popmax 0.0992%, mid) (gnomAD).

What do computational predictors say about FER p.Thr164Pro (c.490A>C)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

FER p.Thr164Pro

c.490A>C · VCV3514614

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0992%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -9.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 302 kb · p 0.76 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0992% Middle Eastern · 6/6,046 alleles

Filtering AF 0.0432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.00593% 95/1,600,912 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0992%	1,008
Remaining individualsnot grpmax-eligible	0.0113%	8,854
European (non-Finnish)	0.00655%	15,276
Admixed American	0.00351%	28,463
South Asian	0.00345%	28,997

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.Thr164Pro
Coding: c.490A>C
MANE Select: NM_005246
Type: single nucleotide variant
Location: chr5:108867775 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.29 · 2 PDB
Residue 164: the f-bar domain; the 'important for interaction with membranes containing phosphoinositides' region

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

Similar variants

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
FER p.Asn261Ser 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-thr164pro (accessed [today's date]).

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