Is EFL1 p.Thr1069Ala (c.3205A>G) pathogenic?

EFL1 p.Thr1069Ala (c.3205A>G) is classified Conflicting classifications of pathogenicity in EFL1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.0976); Ultra-rare (popmax 0.0111%, eas); Associated with Shwachman-Diamond syndrome.

What condition is associated with EFL1 p.Thr1069Ala (c.3205A>G)?

EFL1 p.Thr1069Ala (c.3205A>G) is associated with Shwachman-Diamond syndrome, Shwachman-Diamond syndrome 2 (ClinVar).

How common is EFL1 p.Thr1069Ala (c.3205A>G) in the general population?

EFL1 p.Thr1069Ala (c.3205A>G) is ultra-rare (popmax 0.0111%, eas) (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.Thr1069Ala (c.3205A>G)?

AlphaMissense predicts likely benign (score 0.0976) — an in-silico prediction, not a clinical call.

EFL1 p.Thr1069Ala

c.3205A>G · rs756494164 · VCV1686817

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0976 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Shwachman-Diamond syndrome

Computational evidence

Protein change
AlphaMissense	0.0976	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -7.67	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 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 34 kb · p 0.0014 · regional, not allelic
Overall
CADD	25.0	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

Grpmax group 0.0111% East Asian · 5/44,894 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0018% 29/1,614,026 alleles · ultra-rare exomes 26/1,461,848 · genomes 3/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,979
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
African / African-American	0.00267%	37,454
South Asian	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00144%	69,414

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.Thr1069Ala
Coding: c.3205A>G
MANE Select: NM_024580
dbSNP: rs756494164
Type: single nucleotide variant
Location: chr15:82130531 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.72 · 2 PDB

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

Also linked: Shwachman-Diamond syndrome 2

For Shwachman-Diamond syndrome (Orphanet):

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

Similar variants

EFL1 p.Arg1097Trp Uncertain significance ★★ ⚠ same condition
EFL1 p.Arg970Cys Uncertain significance ★★ ⚠ same condition
EFL1 p.Arg970His 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

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-thr1069ala (accessed [today's date]).

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