Is DHFR p.Pro26Leu (c.77C>T) pathogenic?

DHFR p.Pro26Leu (c.77C>T) is classified Likely pathogenic in DHFR (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.2562); Absent from gnomAD v4.1; Associated with constitutional megaloblastic anemia with severe neurologic disease.

What condition is associated with DHFR p.Pro26Leu (c.77C>T)?

DHFR p.Pro26Leu (c.77C>T) is associated with constitutional megaloblastic anemia with severe neurologic disease (ClinVar).

How common is DHFR p.Pro26Leu (c.77C>T) in the general population?

DHFR p.Pro26Leu (c.77C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DHFR p.Pro26Leu (c.77C>T)?

AlphaMissense predicts likely benign (score 0.2562) — an in-silico prediction, not a clinical call.

DHFR p.Pro26Leu

Q: How is Constitutional megaloblastic anemia with severe neurologic disease inherited?

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

c.77C>T · VCV3381823

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2562 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

constitutional megaloblastic anemia with severe neurologic disease

Computational evidence

Protein change
AlphaMissense	0.2562	likely benign ⚠ discordant with ClinVar
REVEL	0.549	indeterminate
SaProt	LLR -11.53	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.43, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 5,017 bp · p 0.00048 · regional, not allelic
Overall
CADD	26.6	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: DHFR
Protein: p.Pro26Leu
Coding: c.77C>T
MANE Select: NM_000791
Type: single nucleotide variant
Location: chr5:80654413 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 96.32 · 89 PDB
Residue 26: the dhfr domain; a β-strand

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

Disease context

constitutional megaloblastic anemia with severe neurologic disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Constitutional megaloblastic anemia with severe neurologic disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MSH3 p.Arg26Ter Pathogenic/Likely pathogenic ★★ same residue
MSH3 p.Arg26Gln Uncertain significance ★★ ⚠ same residue
MSH3 p.Arg26Pro Uncertain significance ★★ same residue
MSH3 p.Arg26Leu Uncertain significance ★ ⚠ same residue
MSH3 p.Arg26= Likely benign ★ same residue
DHFR p.Met112Arg Uncertain significance ★ ⚠ same condition
DHFR p.Asp153Val Pathogenic ⚠ same condition
DHFR p.Gly18Val 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/dhfr-p-pro26leu (accessed [today's date]).

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