Is MTHFD1 p.Ser49Phe (c.146C>T) pathogenic?

MTHFD1 p.Ser49Phe (c.146C>T) is classified Pathogenic/Likely pathogenic in MTHFD1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.9534); Ultra-rare (popmax 0.0252%, nfe); Associated with MTHFD1-related disorder.

What condition is associated with MTHFD1 p.Ser49Phe (c.146C>T)?

MTHFD1 p.Ser49Phe (c.146C>T) is associated with MTHFD1-related disorder, neural tube defects, folate-sensitive, severe combined immunodeficiency (ClinVar).

How common is MTHFD1 p.Ser49Phe (c.146C>T) in the general population?

MTHFD1 p.Ser49Phe (c.146C>T) is ultra-rare (popmax 0.0252%, nfe) (gnomAD).

What do computational predictors say about MTHFD1 p.Ser49Phe (c.146C>T)?

AlphaMissense predicts likely pathogenic (score 0.9534) — an in-silico prediction, not a clinical call.

MTHFD1 p.Ser49Phe

c.146C>T · rs370444838 · VCV446306

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9534 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

MTHFD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9534	likely pathogenic ✓ concordant with ClinVar
REVEL	0.442	indeterminate
SaProt	LLR -16.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.79, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · regional, not allelic
Overall
CADD	32.0	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 0.0252% European (non-Finnish) · 297/1,179,284 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.0193% 312/1,612,804 alleles · ultra-rare exomes 296/1,460,654 · genomes 16/152,150 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0252%	3,971
Remaining individualsnot grpmax-eligible	0.0144%	6,939
Admixed American	0.00667%	14,998
African / African-American	0.00267%	37,448

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: MTHFD1
Protein: p.Ser49Phe
Coding: c.146C>T
MANE Select: NM_005956
dbSNP: rs370444838
Type: single nucleotide variant
Location: chr14:64411109 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 49: a UniProt-annotated variant site (in cimah); the 'methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (d/c) domain' region; an α-helix

Full MTHFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MTHFD1-related disorder

Also linked: neural tube defects, folate-sensitive severe combined immunodeficiency combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Similar variants

MTHFD1 c.727+1G>A Pathogenic/Likely pathogenic ★★ same condition
MTHFD1 p.Arg173Cys Pathogenic/Likely pathogenic ★★ same condition
MTHFD1 p.Gln100Ter Likely pathogenic ★★ same condition
MTHFD1 p.Glu225Ter Pathogenic ★★ same condition
MTHFD1 p.Arg366Trp Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Ile391Val Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Ile464Val Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Ile862Val 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/mthfd1-p-ser49phe (accessed [today's date]).

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