Is FTL p.Phe38Ser (c.113T>C) pathogenic?

FTL p.Phe38Ser (c.113T>C) is classified Uncertain significance in FTL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-22). AlphaMissense: likely pathogenic (0.9055); Very rare (popmax 6.2e-05%); Associated with hereditary hyperferritinemia with congenital cataracts.

How common is FTL p.Phe38Ser (c.113T>C) in the general population?

FTL p.Phe38Ser (c.113T>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about FTL p.Phe38Ser (c.113T>C)?

AlphaMissense predicts likely pathogenic (score 0.9055) — an in-silico prediction, not a clinical call.

FTL p.Phe38Ser

Q: What condition is associated with FTL p.Phe38Ser (c.113T>C)?

FTL p.Phe38Ser (c.113T>C) is associated with hereditary hyperferritinemia with congenital cataracts, neuroferritinopathy (ClinVar).

Q: How is Hereditary hyperferritinemia-cataract syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.113T>C · rs2038445005 · VCV1509909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9055 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hyperferritinemia with congenital cataracts

Computational evidence

Protein change
AlphaMissense	0.9055	likely pathogenic · top 8% in FTL
REVEL	0.766	pathogenic-leaning
SaProt	LLR -12.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,224 bp · p 0.0076 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 6.2e-05%

Overall 6.2e-05% 1/1,614,142 alleles · very rare exomes 1/1,461,846 · genomes 0/152,296 · joint denominator

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: FTL
Protein: p.Phe38Ser
Coding: c.113T>C
MANE Select: NM_000146
dbSNP: rs2038445005
Type: single nucleotide variant
Location: chr19:48965780 (GRCh38)
Gene constraint: LOEUF 1.552 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 96.69 · 17 PDB
Residue 38: an α-helix; the ferritin-like diiron domain

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

Disease context

hereditary hyperferritinemia with congenital cataracts — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroferritinopathy

For Hereditary hyperferritinemia-cataract syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

FTL c.-149G>C Pathogenic/Likely pathogenic ★★ same condition
FTL c.-150C>A Pathogenic/Likely pathogenic ★★ same condition
FTL c.-157G>A Pathogenic/Likely pathogenic ★★ same condition
FTL c.-160A>G Pathogenic ★★ same condition
FTL c.-161C>T Pathogenic/Likely pathogenic ★★ same condition
FTL c.-164C>A Pathogenic/Likely pathogenic ★★ same condition
FTL c.-167C>T Pathogenic ★★ same condition
FTL c.-168G>A Pathogenic/Likely pathogenic ★★ same condition

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/ftl-p-phe38ser (accessed [today's date]).

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