Is FER p.Ala438Ser (c.1312G>T) pathogenic?

FER p.Ala438Ser (c.1312G>T) is classified Uncertain significance in FER (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.067); Ultra-rare (popmax 0.0134%, eas).

How common is FER p.Ala438Ser (c.1312G>T) in the general population?

FER p.Ala438Ser (c.1312G>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about FER p.Ala438Ser (c.1312G>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

FER p.Ala438Ser

c.1312G>T · VCV4256745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -4.73	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 0.95	GERP -3, phastCons 0.004
Regional constraint	o/e 0.99	unconstrained · MANE · 302 kb · p 0.76 · regional, not allelic
Overall
CADD	2.816	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 0.0134% East Asian · 6/44,762 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.000434% 7/1,611,444 alleles · ultra-rare exomes 3/1,459,502 · genomes 4/151,942 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,460
Admixed American	0.00167%	59,928

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.Ala438Ser
Coding: c.1312G>T
MANE Select: NM_005246
Type: single nucleotide variant
Location: chr5:108946205 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.29 · 2 PDB

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.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
FER p.Asn66Ser 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-ala438ser (accessed [today's date]).

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