Is EFL1 p.Ser93Pro (c.277T>C) pathogenic?

EFL1 p.Ser93Pro (c.277T>C) is classified Conflicting classifications of pathogenicity in EFL1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-03-30). AlphaMissense: likely pathogenic (0.9941); Absent from gnomAD v4.1; Associated with Shwachman-Diamond syndrome 2.

What condition is associated with EFL1 p.Ser93Pro (c.277T>C)?

EFL1 p.Ser93Pro (c.277T>C) is associated with Shwachman-Diamond syndrome 2 (ClinVar).

How common is EFL1 p.Ser93Pro (c.277T>C) in the general population?

EFL1 p.Ser93Pro (c.277T>C) is absent from gnomAD v4.1 (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.Ser93Pro (c.277T>C)?

AlphaMissense predicts likely pathogenic (score 0.9941) — an in-silico prediction, not a clinical call.

EFL1 p.Ser93Pro

c.277T>C · VCV3381490

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9941 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shwachman-Diamond syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9941	likely pathogenic · top 3% in EFL1
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -12.33	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 11	phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 21 kb · p 3.2e-07 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EFL1
Protein: p.Ser93Pro
Coding: c.277T>C
MANE Select: NM_024580
Type: single nucleotide variant
Location: chr15:82241371 (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 93: the tr-type g domain; a binding site

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

Disease context

Shwachman-Diamond syndrome 2 — 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.Arg970Cys Uncertain significance ★★ ⚠ same condition
EFL1 p.Gly850Ser Uncertain significance ★★ ⚠ same condition
EFL1 p.His449Tyr Uncertain significance ★★ ⚠ same condition
EFL1 p.Ile411Asn Uncertain significance ★★ ⚠ same condition
EFL1 p.Ile742Val Uncertain significance ★★ ⚠ same condition
EFL1 p.Leu263Val Uncertain significance ★★ ⚠ same condition
EFL1 p.Leu878Ile Uncertain significance ★★ ⚠ same condition
EFL1 c.2990-36T>C Benign ★★ 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-ser93pro (accessed [today's date]).

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