Is EFL1 p.Ser100Phe (c.299C>T) pathogenic?

EFL1 p.Ser100Phe (c.299C>T) is classified Uncertain significance in EFL1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-06-26). AlphaMissense: likely pathogenic (0.7685); Very rare (popmax 0.00167%, amr); Associated with Shwachman-Diamond syndrome.

What condition is associated with EFL1 p.Ser100Phe (c.299C>T)?

EFL1 p.Ser100Phe (c.299C>T) is associated with Shwachman-Diamond syndrome (ClinVar).

How common is EFL1 p.Ser100Phe (c.299C>T) in the general population?

EFL1 p.Ser100Phe (c.299C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Shwachman-Diamond syndrome inherited?

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

What do computational predictors say about EFL1 p.Ser100Phe (c.299C>T)?

AlphaMissense predicts likely pathogenic (score 0.7685) — an in-silico prediction, not a clinical call.

EFL1 p.Ser100Phe

c.299C>T · rs747935218 · VCV3061307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shwachman-Diamond syndrome

Computational evidence

Protein change
AlphaMissense	0.7685	likely pathogenic
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -10.19	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 12	phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 21 kb · p 3.2e-07 · regional, not allelic
Overall
CADD	31.0	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 0.00167% Admixed American · 1/60,012 alleles

Overall 0.000186% 3/1,613,980 alleles · very rare exomes 3/1,461,672 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
African / African-American	0.00133%	75,044
European (non-Finnish)	8.48e-05%	1,179,898

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: EFL1
Protein: p.Ser100Phe
Coding: c.299C>T
MANE Select: NM_024580
dbSNP: rs747935218
Type: single nucleotide variant
Location: chr15:82241349 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.72 · 2 PDB
Residue 100: the tr-type g domain

Full EFL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Shwachman-Diamond syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Shwachman-Diamond syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Italy)

Similar variants

EFL1 p.Ser100= Likely benign ★ same residue
EFL1 p.Arg1097Trp Uncertain significance ★★ ⚠ same condition
EFL1 p.Arg970His Uncertain significance ★★ ⚠ same condition
EFL1 p.Leu878Ile Uncertain significance ★★ ⚠ same condition
EFL1 p.Arg754Ter Likely pathogenic ★ same condition
EFL1 p.His30Arg Likely pathogenic ★ same condition
EFL1 p.Phe505Ser Likely pathogenic ★ same condition
EFL1 c.245-12A>G 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/efl1-p-ser100phe (accessed [today's date]).

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