Is ST14 p.Ser449Phe (c.1346C>T) pathogenic?

ST14 p.Ser449Phe (c.1346C>T) is classified Uncertain significance in ST14 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-06-27). AlphaMissense: likely benign (0.222); Ultra-rare (popmax 0.0176%, sas); Associated with Inborn genetic diseases.

What condition is associated with ST14 p.Ser449Phe (c.1346C>T)?

ST14 p.Ser449Phe (c.1346C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ST14 p.Ser449Phe (c.1346C>T) in the general population?

ST14 p.Ser449Phe (c.1346C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about ST14 p.Ser449Phe (c.1346C>T)?

AlphaMissense predicts likely benign (score 0.222) — an in-silico prediction, not a clinical call.

ST14 p.Ser449Phe

c.1346C>T · rs777342350 · VCV1878747

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.222 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.222	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 50 kb · p 0.00036 · regional, not allelic
Overall
CADD	24.4	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 0.0176% South Asian · 16/91,084 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00644% 104/1,614,112 alleles · ultra-rare exomes 98/1,461,880 · genomes 6/152,232 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,693
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00686%	14,569
African / African-American	0.00133%	74,938

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: ST14
Protein: p.Ser449Phe
Coding: c.1346C>T
MANE Select: NM_021978
dbSNP: rs777342350
Type: single nucleotide variant
Location: chr11:130196692 (GRCh38)
Gene constraint: LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.23 · 25 PDB

Full ST14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ST14 p.Ala557Thr Uncertain significance ★★ ⚠ same condition
ST14 p.Arg227Gly Uncertain significance ★★ ⚠ same condition
ST14 p.Gly272Ser Uncertain significance ★★ ⚠ same condition
ST14 p.Gly642Ser Uncertain significance ★★ ⚠ same condition
ST14 p.Lys743Asn Uncertain significance ★★ ⚠ same condition
ST14 p.Pro526Leu Uncertain significance ★★ ⚠ same condition
ST14 p.Thr419Ala Uncertain significance ★★ ⚠ same condition
ST14 p.Thr478Ile Uncertain significance ★★ ⚠ 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/st14-p-ser449phe (accessed [today's date]).

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